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  • 1. At a Glance 2 1 Fundamentals and Cell Physiology 42 2 Nerve and Muscle, Physical Work 78 3 Autonomic Nervous System (ANS) 88 4 Blood 106 5 Respiration 138 6 Acid–Base Homeostasis 148 7 Kidneys, Salt, and Water Balance 186 8 Cardiovascular System 222 9 Thermal Balance and Thermoregulation 226 10 Nutrition and Digestion 266 11 Hormones and Reproduction 310 12 Central Nervous System and Senses 372 13 Appendix 391 Further Reading 394 IndexDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 2. II Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 3. Color Atlas of Physiology 5th edition, completely revised and expanded Agamemnon Despopoulos, M.D. Professor Formerly: Ciba Geigy Basel Stefan Silbernagl, M.D. Professor Head of Department Institute of Physiology University of Wuerzburg Wuerzburg, Germany 186 color plates by Ruediger Gay and Astried Rothenburger Thieme Stuttgart · New YorkDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 4. Library of Congress Cataloging-in-Publication Important Note: Medicine is an ever-changing Data science undergoing continual development. is available from the publisher Research and clinical experience are continu- ally expanding our knowledge, in particular our knowledge of proper treatment and drug 1st German edition 1979 1st Czech edition 1984 therapy. Insofar as this book mentions any do- 2nd German edition 1983 2nd Czech edition 1994 sage or application, readers may rest assured 3rd German edition 1988 1st French edition 1985 that the authors, editors, and publishers have 4th German edition 1991 2nd French edition 1992 5th German edition 2001 3rd French edition 2001 made every effort to ensure that such refe- 1st English edition 1981 rences are in accordance with the state of 1st Turkish edition 1986 2nd English edition 1984 2nd Turkish edition 1997 knowledge at the time of production of the 3rd English edition 1986 book. 4th English edition 1991 1st Greek edition 1989 Nevertheless, this does not involve, imply, 1st Dutch edition 1981 1st Chinese edition 1991 or express any guarantee or responsibility on 2nd Dutch edition 2001 1st Polish edition 1994 the part of the publishers in respect to any do- 1st Italian edition 1981 1st Hungarian edition 1994 sage instructions and forms of applications 2nd Italian edition 2001 2nd Hungarian edition 1996 stated in the book. Every user is requested to 1st Japanese edition 1982 1st Indonesion edition 2000 examine carefully the manufacturers’ leaflets 2nd Japanese edition 1992 accompanying each drug and to check, if 1st Spanish edition 1982 2nd Spanish edition 1985 necessary in consultation with a physician or 3rd Spanish edition 1994 specialist, whether the dosage schedules men- 4th Spanish edition 2001 tioned therein or the contraindications stated by the manufacturers differ from the state- ments made in the present book. Such exami- This book is an authorized translation of the nation is particularly important with drugs 5th German edition published and copy- that are either rarely used or have been newly righted 2001 by Georg Thieme Verlag, Stutt- released on the market. Every dosage schedule gart, Germany. or every form of application used is entirely at Title of the German edition: the user’s own risk and responsibility. The au- Taschenatlas der Physiologie thors and publishers request every user to re- port to the publishers any discrepancies or Translated by Suzyon O’Neal Wandrey, Berlin, inaccuracies noticed. Germany Some of the product names, patents, and Illustrated by Atelier Gay + Rothenburger, Ster- registered designs referred to in this book are nenfels, Germany in fact registered trademarks or proprietary names even though specific reference to this 1981, 2003 Georg Thieme Verlag fact is not always made in the text. Therefore, Rüdigerstraße 14, D-70469 Stuttgart, Germany the appearance of a name without designation http://www.thieme.de as proprietary is not to be construed as a repre- Thieme New York, 333 Seventh Avenue, sentation by the publisher that it is in the New York, N.Y. 10001, U.S.A. public domain. http://www.thieme.com This book, including all parts thereof, is le- gally protected by copyright. Any use, exploita- Cover design: Cyclus, Stuttgart tion, or commercialization outside the narrow Typesetting by: Druckhaus Götz GmbH, limits set by copyright legislation, without the Ludwigsburg, Germany publisher’s consent, is illegal and liable to pro- Printed in Germany by: Appl Druck secution. This applies in particular to photostat GmbH & Co. KG, Wemding, Germany reproduction, copying, mimeographing or duplication of any kind, translating, prepara-IV ISBN 3-13-545005-8 (GTV) tion of microfilms, and electronic data pro- ISBN 1-58890-061-4 (TNY) 1 2 3 4 5 cessing and storage. Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 5. Preface to the Fifth EditionThe base of knowledge in many sectors of phy- Prof. C. von Campenhausen, Mainz, Dr. M. Fi-siology has grown considerably in magnitude scher, Mainz, Prof. K.H. Plattig, Erlangen, andand in depth since the last edition of this book Dr. C. Walther, Marburg, and from my collea-was published. Many advances, especially the gues and staff at the Institute in Würzburg. Itrapid progress in sequencing the human ge- was again a great pleasure to work with Rüdi-nome and its gene products, have brought ger Gay and Astried Rothenburger, to whom Icompletely new insight into cell function and am deeply indebted for revising practically allcommunication. This made it necessary to edit the illustrations in the book and for designing aand, in some cases, enlarge many parts of the number of new color plates. Their extraordina-book, especially the chapter on the fundamen- ry enthusiasm and professionalism played atals of cell physiology and the sections on decisive role in the materialization of this newneurotransmission, mechanisms of intracellu- edition. To them I extend my sincere thanks. Ilar signal transmission, immune defense, and would also like to thank Suzyon O’Neal Wan-the processing of sensory stimuli. A list of phy- drey for her outstanding translation. I greatlysiological reference values and important for- appreciate her capable and careful work. I ammulas were added to the appendix for quick also indebted to the publishing staff, especiallyreference. The extensive index now also serves Marianne Mauch, an extremely competent andas a key to abbreviations used in the text. motivated editor, and Gert Krüger for invalu- Some of the comments explaining the con- able production assistance. I would also like tonections between pathophysiological princi- thank Katharina Völker for her ever observantples and clinical dysfunctions had to be slight- and conscientious assistance in preparing thely truncated and set in smaller print. However, index.this base of knowledge has also grown consi- I hope that the 5th Edition of the Color Atlasderably for the reasons mentioned above. To of Physiology will prove to be a valuable tool formake allowances for this, a similarly designed helping students better understand physiolog-book, the Color Atlas of Pathophysiology ical correlates, and that it will be a valuable re-(S. Silbernagl and F. Lang, Thieme), has now ference for practicing physicians and scien-been introduced to supplement the well- tists, to help them recall previously learned in-established Color Atlas of Physiology. formation and gain new insights in physiology. I am very grateful for the many helpful com-ments from attentive readers (including myson Jakob) and for the welcome feedback from Würzburg, December 2002my peers, especially Prof. H. Antoni, Freiburg, Stefan Silbernagl* V* e-mail: stefan.silbernagl@mail.uni-wuerzburg.de Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 6. Preface to the First Edition In the modern world, visual pathways have A book of this nature is inevitably deriva- outdistanced other avenues for informational tive, but many of the representations are new input. This book takes advantage of the econo- and, we hope, innovative. A number of people my of visual representation to indicate the si- have contributed directly and indirectly to the multaneity and multiplicity of physiological completion of this volume, but none more phenomena. Although some subjects lend than Sarah Jones, who gave much more than themselves more readily than others to this editorial assistance. Acknowledgement of treatment, inclusive rather than selective helpful criticism and advice is due also to Drs. coverage of the key elements of physiology has R. Greger, A. Ratner, J. Weiss, and S. Wood, and been attempted. Prof. H. Seller. We are grateful to Joy Wieser for Clearly, this book of little more than 300 her help in checking the proofs. Wolf-Rüdiger pages, only half of which are textual, cannot be and Barbara Gay are especially recognized, not considered as a primary source for the serious only for their art work, but for their conceptual student of physiology. Nevertheless, it does contributions as well. The publishers, Georg contain most of the basic principles and facts Thieme Verlag and Deutscher Taschenbuch taught in a medical school introductory Verlag, contributed valuable assistance based course. Each unit of text and illustration can on extensive experience; an author could wish serve initially as an overview for introduction for no better relationship. Finally, special to the subject and subsequently as a concise recognition to Dr. Walter Kumpmann for in- review of the material. The contents are as cur- spiring the project and for his unquestioning rent as the publishing art permits and include confidence in the authors. both classical information for the beginning students as well as recent details and trends Basel and Innsbruck, Summer 1979 for the advanced student. Agamemnon Despopoulos Stefan SilbernaglVI Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 7. From the Preface to the Third EditionThe first German edition of this book was al-ready in press when, on November 2nd, 1979,Agamennon Despopoulos and his wife, SarahJones-Despopoulos put to sea from Bizerta, Tu-nisia. Their intention was to cross the Atlanticin their sailing boat. This was the last that wasever heard of them and we have had to aban-don all hope of seeing them again. Without the creative enthusiasm of Aga-mennon Despopoulos, it is doubtful whetherthis book would have been possible; withouthis personal support it has not been easy tocontinue with the project. Whilst keeping inmind our original aims, I have completely re-vised the book, incorporating the latest advan-ces in the field of physiology as well as the wel-come suggestions provided by readers of the Dr. Agamemnon Despopoulosearlier edition, to whom I extend my thanks fortheir active interest. Born 1924 in New York; Professor of Physiology at the University of New Mexico. Albuquerque, USA, until 1971; Würzburg, Fall 1985 thereafter scientific adviser to CIBA-GEIGY, Basel. Stefan Silbernagl VII Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 8. VIII Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 9. Table of Contents Fundamentals and Cell Physiology 2 1 The Body: an Open System with an Internal Environment · · · 2 Control and Regulation · · · 4 The Cell · · · 8 Transport In, Through, and Between Cells · · · 16 Passive Transport by Means of Diffusion · · · 20 Osmosis, Filtration, and Convection · · · 24 Active Transport · · · 26 Cell Migration · · · 30 Electrical Membrane Potentials and Ion Channels · · · 32 Role of Ca2+ in Cell Regulation · · · 36 Energy Production and Metabolism · · · 38 Nerve and Muscle, Physical Work 42 2 Neuron Structure and Function · · · 42 Resting Membrane Potential · · · 44 Action Potential · · · 46 Propagation of Action Potentials in Nerve Fiber · · · 48 Artificial Stimulation of Nerve Cells · · · 50 Synaptic Transmission · · · 50 Motor End-plate · · · 56 Motility and Muscle Types · · · 58 Motor Unit of Skeletal Muscle · · · 58 Contractile Apparatus of Striated Muscle · · · 60 Contraction of Striated Muscle · · · 62 Mechanical Features of Skeletal Muscle · · · 66 Smooth Muscle · · · 70 Energy Supply for Muscle Contraction · · · 72 Physical Work · · · 74 Physical Fitness and Training · · · 76 Autonomic Nervous System (ANS) 78 3 Organization of the Autonomic Nervous System · · · 78 Acetylcholine and Cholinergic Transmission · · · 82 Catecholamine, Adrenergic Transmission and Adrenoceptors · · · 84 Adrenal Medulla · · · 86 Non-cholinergic, Non-adrenergic Transmitters · · · 86 IXDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 10. Blood 88 4 Composition and Function of Blood · · · 88 Iron Metabolism and Erythropoiesis · · · 90 Flow Properties of Blood · · · 92 Plasma, Ion Distribution · · · 92 Immune System · · · 94 Hypersensitivity Reactions (Allergies) · · · 100 Blood Groups · · · 100 Hemostasis · · · 102 Fibrinolysis and Thromboprotection · · · 104 Respiration 106 5 Lung Function, Respiration · · · 106 Mechanics of Breathing · · · 108 Purification of Respiratory Air · · · 110 Artificial Respiration · · · 110 Pneumothorax · · · 110 Lung Volumes and their Measurement · · · 112 Dead Space, Residual Volume, and Airway Resistance · · · 114 Lung–Chest Pressure—Volume Curve, Respiratory Work · · · 116 Surface Tension, Surfactant · · · 118 Dynamic Lung Function Tests · · · 118 Pulmonary Gas Exchange · · · 120 Pulmonary Blood Flow, Ventilation–Perfusion Ratio · · · 122 CO2 Transport in Blood · · · 124 CO2 Binding in Blood · · · 126 CO2 in Cerebrospinal Fluid · · · 126 Binding and Transport of O2 in Blood · · · 128 Internal (Tissue) Respiration, Hypoxia · · · 130 Respiratory Control and Stimulation · · · 132 Effects of Diving on Respiration · · · 134 Effects of High Altitude on Respiration · · · 136 Oxygen Toxicity · · · 136 Acid–Base Homeostasis 138 6 pH, pH Buffers, Acid–Base Balance · · · 138 Bicarbonate/Carbon Dioxide Buffer · · · 140 Acidosis and Alkalosis · · · 142 Assessment of Acid–Base Status · · · 146 Kidneys, Salt, and Water Balance 148 7 Kidney Structure and Function · · · 148 Renal Circulation · · · 150 Glomerular Filtration and Clearance · · · 152X Transport Processes at the Nephron · · · 154 Reabsorption of Organic Substances · · · 158 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 11. Excretion of Organic Substances · · · 160 Reabsorption of Na+ and Cl– · · · 162 Reabsorption of Water, Formation of Concentrated Urine · · · 164 Body Fluid Homeostasis · · · 168 Salt and Water Regulation · · · 170 Diuresis and Diuretics · · · 172 Disturbances of Salt and Water Homeostasis · · · 172 The Kidney and Acid–Base Balance · · · 174 Reabsorption and Excretion of Phosphate, Ca2+ and Mg2+ · · · 178 Potassium Balance · · · 180 Tubuloglomerular Feedback, Renin–Angiotensin System · · · 184 Cardiovascular System 186 8 Overview · · · 186 Blood Vessels and Blood Flow · · · 188 Cardiac Cycle · · · 190 Cardiac Impulse Generation and Conduction · · · 192 Electrocardiogram (ECG) · · · 196 Excitation in Electrolyte Disturbances · · · 198 Cardiac Arrhythmias · · · 200 Ventricular Pressure–Volume Relationships · · · 202 Cardiac Work and Cardiac Power · · · 202 Regulation of Stroke Volume · · · 204 Venous Return · · · 204 Arterial Blood Pressure · · · 206 Endothelial Exchange Processes · · · 208 Myocardial Oxygen Supply · · · 210 Regulation of the Circulation · · · 212 Circulatory Shock · · · 218 Fetal and Neonatal Circulation · · · 220 Thermal Balance and Thermoregulation 222 9 Thermal Balance · · · 222 Thermoregulation · · · 224 Nutrition and Digestion 226 10 Nutrition · · · 226 Energy Metabolism and Calorimetry · · · 228 Energy Homeostasis and Body Weight · · · 230 Gastrointestinal (GI) Tract: Overview, Immune Defense and Blood Flow · · · 232 Neural and Hormonal Integration · · · 234 Saliva · · · 236 Deglutition · · · 238 Vomiting · · · 238 Stomach Structure and Motility · · · 240 Gastric Juice · · · 242 XI Small Intestinal Function · · · 244Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 12. Pancreas · · · 246 Bile · · · 248 Excretory Liver Function—Bilirubin · · · 250 Lipid Digestion · · · 252 Lipid Distribution and Storage · · · 254 Digestion and Absorption of Carbohydrates and Protein · · · 258 Vitamin Absorption · · · 260 Water and Mineral Absorption · · · 262 Large Intestine, Defecation, Feces · · · 264 Hormones and Reproduction 266 11 Integrative Systems of the Body · · · 266 Hormones · · · 268 Humoral Signals: Control and Effects · · · 272 Cellular Transmission of Signals from Extracellular Messengers · · · 274 Hypothalamic–Pituitary System · · · 280 Carbohydrate Metabolism and Pancreatic Hormones · · · 282 Thyroid Hormones · · · 286 Calcium and Phosphate Metabolism · · · 290 Biosynthesis of Steroid Hormones · · · 294 Adrenal Cortex and Glucocorticoid Synthesis · · · 296 Oogenesis and the Menstrual Cycle · · · 298 Hormonal Control of the Menstrual Cycle · · · 300 Estrogens · · · 302 Progesterone · · · 302 Prolactin and Oxytocin · · · 303 Hormonal Control of Pregnancy and Birth · · · 304 Androgens and Testicular Function · · · 306 Sexual Response, Intercourse and Fertilization · · · 308 Central Nervous System and Senses 310 12 Central Nervous System · · · 310 Cerebrospinal Fluid · · · 310 Stimulus Reception and Processing · · · 312 Sensory Functions of the Skin · · · 314 Proprioception, Stretch Reflex · · · 316 Nociception and Pain · · · 318 Polysynaptic Reflexes · · · 320 Synaptic Inhibition · · · 320 Central Conduction of Sensory Input · · · 322 Motor System · · · 324 Hypothalamus, Limbic System · · · 330 Cerebral Cortex, Electroencephalogram (EEG) · · · 332 Sleep–Wake Cycle, Circadian Rhythms · · · 334 Consciousness, Memory, Language · · · 336 Glia · · · 338 Sense of Taste · · · 338XII Sense of Smell · · · 340 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 13. Sense of Balance · · · 342 Eye Structure, Tear Fluid, Aqueous Humor · · · 344 Optical Apparatus of the Eye · · · 346 Visual Acuity, Photosensors · · · 348 Adaptation of the Eye to Different Light Intensities · · · 352 Retinal Processing of Visual Stimuli · · · 354 Color Vision · · · 356 Visual Field, Visual Pathway, Central Processing of Visual Stimuli · · · 358 Eye Movements, Stereoscopic Vision, Depth Perception · · · 360 Physical Principles of Sound—Sound Stimulus and Perception · · · 362 Conduction of Sound, Sound Sensors · · · 364 Central Processing of Acoustic Information · · · 368 Voice and Speech · · · 370 Appendix 372 13 Dimensions and Units · · · 372 Powers and Logarithms · · · 380 Graphic Representation of Data · · · 381 The Greek Alphabet · · · 384 Reference Values in Physiology · · · 384 Important Equations in Physiology · · · 388 Further Reading 391 Index 394 XIIIDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 14. 1 Fundamentals and Cell Physiology “. . . If we break up a living organism by isolating its different parts, it is only for the sake of ease in analysis and by no means in order to conceive them separately. Indeed, when we wish to ascribe to a physiological quality its value and true significance, we must always refer it to the whole and draw our final conclusions only in relation to its effects on the whole.” Claude Bernard (1865) ganism is capable of eliciting motor responses The Body: an Open System with an to signals from the environment. This is Internal Environment achieved by moving its pseudopodia or The existence of unicellular organisms is the flagella, for example, in response to changes in epitome of life in its simplest form. Even the food concentration. simple protists must meet two basic but essen- The evolution from unicellular organisms to tially conflicting demands in order to survive. multicellular organisms, the transition from A unicellular organism must, on the one hand, specialized cell groups to organs, the emer- isolate itself from the seeming disorder of its gence of the two sexes, the coexistence of in- inanimate surroundings, yet, as an “open sys- dividuals in social groups, and the transition tem” ( p. 40), it is dependent on its environ- from water to land have tremendously in- ment for the exchange of heat, oxygen, creased the efficiency, survival, radius of ac- nutrients, waste materials, and information. tion, and independence of living organisms. “Isolation” is mainly ensured by the cell This process required the simultaneous devel- membrane, the hydrophobic properties of opment of a complex infrastructure within the which prevent the potentially fatal mixing of organism. Nonetheless, the individual cells of hydrophilic components in watery solutions the body still need a milieu like that of the inside and outside the cell. Protein molecules primordial sea for life and survival. Today, the within the cell membrane ensure the perme- extracellular fluid is responsible for providing ability of the membrane barrier. They may constant environmental conditions ( B), but exist in the form of pores (channels) or as more the volume of the fluid is no longer infinite. In complex transport proteins known as carriers fact, it is even smaller than the intracellular ( p. 26 ff.). Both types are selective for cer- volume ( p. 168). Because of their metabolic tain substances, and their activity is usually activity, the cells would quickly deplete the regulated. The cell membrane is relatively well oxygen and nutrient stores within the fluids permeable to hydrophobic molecules such as and flood their surroundings with waste prod- gases. This is useful for the exchange of O2 and ucts if organs capable of maintaining a stable CO2 and for the uptake of lipophilic signal sub- internal environment had not developed. This stances, yet exposes the cell to poisonous gases is achieved through homeostasis, a process by such as carbon monoxide (CO) and lipophilic which physiologic self-regulatory mecha- noxae such as organic solvents. The cell mem- nisms (see below) maintain steady states in brane also contains other proteins—namely, the body through coordinated physiological receptors and enzymes. Receptors receive sig- activity. Specialized organs ensure the con- nals from the external environment and con- tinuous absorption of nutrients, electrolytes vey the information to the interior of the cell and water and the excretion of waste products (signal transduction), and enzymes enable the via the urine and feces. The circulating blood cell to metabolize extracellular substrates. connects the organs to every inch of the body, Let us imagine the primordial sea as the ex- and the exchange of materials between the ternal environment of the unicellular or- blood and the intercellular spaces (interstices) ganism ( A). This milieu remains more or less creates a stable environment for the cells. Or- constant, although the organism absorbs gans such as the digestive tract and liver ab- nutrients from it and excretes waste into it. In sorb nutrients and make them available by2 spite of its simple structure, the unicellular or- processing, metabolizing and distributing Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 15. A. Unicellular organism in the constant external environment of the primordial sea Substance absorption Signal receptionPrimordial and excretionsea Internal and External Environment Heat Ion exchange Genome Digestion Water O2 Exchange Motility of gases CO2 Excretion Plate 1.1 B. Maintenance of a stable internal environment in humans Integration through External signals nervous system and hormones O2 CO2 Exchange Emission of heat Internal of gases (water, salt) signals Behavior Regulation Lungs Blood Skin Extra- cellular Interstice space Intracellular space Uptake of nutrients, water, salts, etc. Kidney Distribution Excretion of excess – water Waste and – salts toxins Liver Excretion of – acids Digestive 3 tract waste and toxinsDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 16. them throughout the body. The lung is re- Although behavioral science, sociology, and sponsible for the exchange of gases (O2 intake, psychology are disciplines that border on CO2 elimination), the liver and kidney for the physiology, true bridges between them and excretion of waste and foreign substances, and physiology have been established only in ex- the skin for the release of heat. The kidney and ceptional cases. lungs also play an important role in regulating the internal environment, e.g., water content, Control and Regulation osmolality, ion concentrations, pH (kidney, lungs) and O2 and CO2 pressure (lungs) ( B). In order to have useful cooperation between1 Fundamentals and Cell Physiology The specialization of cells and organs for the specialized organs of the body, their func- specific tasks naturally requires integration, tions must be adjusted to meet specific needs. which is achieved by convective transport over In other words, the organs must be subject to long distances (circulation, respiratory tract), control and regulation. Control implies that a humoral transfer of information (hormones), controlled variable such as the blood pressure and transmission of electrical signals in the is subject to selective external modification, nervous system, to name a few examples. for example, through alteration of the heart These mechanisms are responsible for supply rate ( p. 218). Because many other factors and disposal and thereby maintain a stable in- also affect the blood pressure and heart rate, ternal environment, even under conditions of the controlled variable can only be kept con- extremely high demand and stress. Moreover, stant by continuously measuring the current they control and regulate functions that en- blood pressure, comparing it with the refer- sure survival in the sense of preservation of the ence signal (set point), and continuously cor- species. Important factors in this process in- recting any deviations. If the blood pressure clude not only the timely development of re- drops—due, for example, to rapidly standing productive organs and the availability of fertil- up from a recumbent position—the heart rate izable gametes at sexual maturity, but also the will increase until the blood pressure has been control of erection, ejaculation, fertilization, reasonably adjusted. Once the blood pressure and nidation. Others include the coordination has risen above a certain limit, the heart rate of functions in the mother and fetus during will decrease again and the blood pressure will pregnancy and regulation of the birth process normalize. This type of closed-loop control is and the lactation period. called a negative feedback control system or a The central nervous system (CNS) processes control circuit ( C1). It consists of a controller signals from peripheral sensors (single with a programmed set-point value (target sensory cells or sensory organs), activates out- value) and control elements (effectors) that can wardly directed effectors (e.g., skeletal adjust the controlled variable to the set point. muscles), and influences the endocrine glands. The system also includes sensors that continu- The CNS is the focus of attention when study- ously measure the actual value of the con- ing human or animal behavior. It helps us to lo- trolled variable of interest and report it (feed- cate food and water and protects us from heat back) to the controller, which compares the ac- or cold. The central nervous system also plays a tual value of the controlled variable with the role in partner selection, concern for offspring set-point value and makes the necessary ad- even long after their birth, and integration into justments if disturbance-related discrepancies social systems. The CNS is also involved in the have occurred. The control system operates development, expression, and processing of either from within the organ itself (autoregula- emotions such as desire, listlessness, curiosity, tion) or via a superordinate organ such as the wishfulness, happiness, anger, wrath, and central nervous system or hormone glands. envy and of traits such as creativeness, inquisi- Unlike simple control, the elements of a con- tiveness, self-awareness, and responsibility. trol circuit can work rather imprecisely This goes far beyond the scope of physiology— without causing a deviation from the set point which in the narrower sense is the study of the (at least on average). Moreover, control circuits 4 functions of the body—and, hence, of this book. are capable of responding to unexpected dis- Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 17. C. Control circuit Set point value Prescribed set point Controller Actual value = set point ? Negative feedback Control and Regulation I Control signal Actual value Control element 1 Control Sensor element 2 Control Plate 1.2 element n Controlled 1 system Control circuit: principle Disturbance Set point Actual pressure = set point ? Autonomic nervous system Circulatory centers Nerve IX Nerve X Presso- Arterioles sensors Heart rate Venous return Peripheral resistance Blood pressure 2 Control circuit: blood pressure Orthostasis etc. 5Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 18. turbances. In the case of blood pressure regu- tends the settling time ( E, subject no. 3) and lation ( C2), for example, the system can re- can lead to regulatory instability, i.e., a situa- spond to events such as orthostasis ( p. 204) tion where the actual value oscillates back and or sudden blood loss. forth between extremes (unstable oscillation, The type of control circuits described above E, subject no. 4). keep the controlled variables constant when Oscillation of a controlled variable in re- disturbance variables cause the controlled sponse to a disturbance variable can be at- variable to deviate from the set point ( D2). tenuated by either of two mechanisms. First, Within the body, the set point is rarely invaria- sensors with differential characteristics (D1 Fundamentals and Cell Physiology ble, but can be “shifted” when requirements of sensors) ensure that the intensity of the sensor higher priority make such a change necessary. signal increases in proportion with the rate of In this case, it is the variation of the set point deviation of the controlled variable from the that creates the discrepancy between the set point ( p. 312 ff.). Second, feedforward nominal and actual values, thus leading to the control ensures that information regarding the activation of regulatory elements ( D3). expected intensity of disturbance is reported Since the regulatory process is then triggered to the controller before the value of the con- by variation of the set point (and not by distur- trolled variable has changed at all. Feedfor- bance variables), this is called servocontrol or ward control can be explained by example of servomechanism. Fever ( p. 224) and the ad- physiologic thermoregulation, a process in justment of muscle length by muscle spindles which cold receptors on the skin trigger coun- and γ-motor neurons ( p. 316) are examples terregulation before a change in the controlled of servocontrol. value (core temperature of the body) has actu- In addition to relatively simple variables ally occurred ( p. 224). The disadvantage of such as blood pressure, cellular pH, muscle having only D sensors in the control circuit can length, body weight and the plasma glucose be demonstrated by example of arterial pres- concentration, the body also regulates com- sosensors (= pressoreceptors) in acute blood plex sequences of events such as fertilization, pressure regulation. Very slow but steady pregnancy, growth and organ differentiation, changes, as observed in the development of as well as sensory stimulus processing and the arterial hypertension, then escape regulation. motor activity of skeletal muscles, e.g., to In fact, a rapid drop in the blood pressure of a maintain equilibrium while running. The regu- hypertensive patient will even cause a coun- latory process may take parts of a second (e.g., terregulatory increase in blood pressure. purposeful movement) to several years (e.g., Therefore, other control systems are needed to the growth process). ensure proper long-term blood pressure regu- In the control circuits described above, the lation. controlled variables are kept constant on aver- age, with variably large, wave-like deviations. The sudden emergence of a disturbance varia- ble causes larger deviations that quickly nor- malize in a stable control circuit ( E, test sub- ject no. 1). The degree of deviation may be slight in some cases but substantial in others. The latter is true, for example, for the blood glucose concentration, which nearly doubles after meals. This type of regulation obviously functions only to prevent extreme rises and falls (e.g., hyper- or hypoglycemia) or chronic deviation of the controlled variable. More pre- cise maintenance of the controlled variable re- quires a higher level of regulatory sensitivity 6 (high amplification factor). However, this ex- Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 19. D. Control circuit response to disturbance or set point (SP) deviation SP Controller SP Controller SP Controller Sensor Sensor Sensor Controlled Controlled Controlled system Disturbance system Disturbance system Disturb- ance Control and Regulation II Set point Actual value Time Time Time 1 Stable control 2 Strong disturbance 3 Large set point shift E. Blood pressure control after suddenly standing erect 80 Subject 1 Plate 1.3 75 Quick and complete 70 return to baseline 65 100 Subject 2 90 Slow and incomplete adjustment (deviation from set point) Mean arterial pressure (mmHg) 80 100 Subject 3 90 80 Fluctuating adjustment 70 110 Subject 4 100 90 Unstable control 80 10 20 30 40 50 60 70 80 s Reclining Standing 7 (After A. Dittmar & K. Mechelke)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 20. inal. In cell division, this process is the means The Cell by which duplication of genetic information The cell is the smallest functional unit of a (replication) is achieved. living organism. In other words, a cell (and no Messenger RNA (mRNA) is responsible for smaller unit) is able to perform essential vital code transmission, that is, passage of coding functions such as metabolism, growth, move- sequences from DNA in the nucleus (base ment, reproduction, and hereditary transmis- sequence) for protein synthesis in the cytosol sion (W. Roux) ( p. 4). Growth, reproduction, (amino acid sequence) ( C1). mRNA is and hereditary transmission can be achieved formed in the nucleus and differs from DNA in1 Fundamentals and Cell Physiology by cell division. that it consists of only a single strand and that Cell components: All cells consist of a cell it contains ribose instead of deoxyribose, and membrane, cytosol or cytoplasm (ca. 50 vol.%), uracil (U) instead of thymine. In DNA, each and membrane-bound subcellular structures amino acid (e.g., glutamate, E) needed for known as organelles ( A, B). The organelles of synthesis of a given protein is coded by a set of eukaryotic cells are highly specialized. For in- three adjacent bases called a codon or triplet stance, the genetic material of the cell is con- (C–T–C in the case of glutamate). In order to centrated in the cell nucleus, whereas “diges- transcribe the DNA triplet, mRNA must form a tive” enzymes are located in the lysosomes. complementary codon (e.g., G–A–G for gluta- Oxidative ATP production takes place in the mate). The relatively small transfer RNA mitochondria. (tRNA) molecule is responsible for reading the The cell nucleus contains a liquid known codon in the ribosomes ( C2). tRNA contains as karyolymph, a nucleolus, and chromatin. a complementary codon called the anticodon Chromatin contains deoxyribonucleic acids for this purpose. The anticodon for glutamate (DNA), the carriers of genetic information. Two is C–U–C ( E). strands of DNA forming a double helix (up to RNA synthesis in the nucleus is controlled 7 cm in length) are twisted and folded to form by RNA polymerases (types I–III). Their effect chromosomes 10 µm in length. Humans nor- on DNA is normally blocked by a repressor pro- mally have 46 chromosomes, consisting of 22 tein. Phosphorylation of the polymerase oc- autosomal pairs and the chromosomes that curs if the repressor is eliminated (de-repres- determine the sex (XX in females, XY in males). sion) and the general transcription factors at- DNA is made up of a strand of three-part tach to the so-called promoter sequence of the molecules called nucleotides, each of which DNA molecule (T–A–T–A in the case of poly- consists of a pentose (deoxyribose) molecule, a merase II). Once activated, it separates the two phosphate group, and a base. Each sugar strands of DNA at a particular site so that the molecule of the monotonic sugar–phosphate code on one of the strands can be read and backbone of the strands (. . .deoxyribose – transcribed to form mRNA (transcription, phosphate–deoxyribose. . .) is attached to one C1a, D). The heterogeneous nuclear RNA of four different bases. The sequence of bases (hnRNA) molecules synthesized by the poly- represents the genetic code for each of the merase have a characteristic “cap” at their 5! roughly 100 000 different proteins that a cell end and a polyadenine “tail” (A–A–A–. . .) at the produces during its lifetime (gene expression). 3! end ( D). Once synthesized, they are im- In a DNA double helix, each base in one strand mediately “enveloped” in a protein coat, yield- of DNA is bonded to its complementary base in ing heterogeneous nuclear ribonucleoprotein the other strand according to the rule: adenine (hnRNP) particles. The primary RNA or pre- (A) with thymine (T) and guanine (G) with cy- mRNA of hnRNA contains both coding tosine (C). The base sequence of one strand of sequences (exons) and non-coding sequences the double helix ( E) is always a “mirror (introns). The exons code for amino acid image” of the opposite strand. Therefore, one sequences of the proteins to be synthesized, strand can be used as a template for making a whereas the introns are not involved in the new complementary strand, the information coding process. Introns may contain 100 to 8 content of which is identical to that of the orig- 10 000 nucleotides; they are removed from the Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 21. A. Cell organelles (epithelial cell) Tight junction Cell membrane Cytosol Cytoskeleton Lysosome Smooth ER Golgi vesicle Rough ER Mitochondrion Golgi complex Nucleus Chromatin Vacuole The Cell I Nucleolus B. Cell structure (epithelial cell) in electron micrograph Plate 1.4 Cell membrane Brush border 1 µm Vacuole Tight junction Free ribosomes Cell border Mitochondria Lysosomes Rough endoplasmic reticulum Autophagosome Golgi complex Basal labyrinth (with cell membranes) Basal membrane 9 Photo: W. PfallerDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 22. primary mRNA strand by splicing ( C1b, D) brane of the endoplasmic reticulum (ER), and then degraded. The introns, themselves, which is described below ( F). contain the information on the exact splicing The mRNA exported from the nucleus site. Splicing is ATP-dependent and requires travels to the ribosomes ( C1), which either the interaction of a number of proteins within float freely in the cytosol or are bound to the a ribonucleoprotein complex called the cytosolic side of the endoplasmic reticulum, as spliceosome. Introns usually make up the lion’s described below. Each ribosome is made up of share of pre-mRNA molecules. For example, dozens of proteins associated with a number they make up 95% of the nucleotide chain of of structural RNA molecules called ribosomal1 Fundamentals and Cell Physiology coagulation factor VIII, which contains 25 in- RNA (rRNA). The two subunits of the ribosome trons. mRNA can also be modified (e.g., are first transcribed from numerous rRNA through methylation) during the course of genes in the nucleolus, then separately exit the posttranscriptional modification. cell nucleus through the nuclear pores. As- RNA now exits the nucleus through nuc- sembled together to form a ribosome, they lear pores (around 4000 per nucleus) and en- now comprise the biochemical “machinery” ters the cytosol ( C1c). Nuclear pores are for protein synthesis (translation) ( C2). Syn- high-molecular-weight protein complexes thesis of a peptide chain also requires the pres- (125 MDa) located within the nuclear en- ence of specific tRNA molecules (at least one velope. They allow large molecules such as for each of the 21 proteinogenous amino transcription factors, RNA polymerases or cy- acids). In this case, the target amino acid is toplasmic steroid hormone receptors to pass bound to the C–C–A end of the tRNA molecule into the nucleus, nuclear molecules such as (same in all tRNAs), and the corresponding an- mRNA and tRNA to pass out of the nucleus, and ticodon that recognizes the mRNA codon is lo- other molecules such as ribosomal proteins to cated at the other end ( E). Each ribosome travel both ways. The (ATP-dependent) pas- has two tRNA binding sites: one for the last in- sage of a molecule in either direction cannot corporated amino acid and another for the one occur without the help of a specific signal that beside it (not shown in E). Protein synthesis guides the molecule into the pore. The above- begins when the start codon is read and ends mentioned 5! cap is responsible for the exit of once the stop codon has been reached. The ri- mRNA from the nucleus, and one or two bosome then breaks down into its two sub- specific sequences of a few (mostly cationic) units and releases the mRNA ( C2). Ribo- amino acids are required as the signal for the somes can add approximately 10–20 amino entry of proteins into the nucleus. These acids per second. However, since an mRNA sequences form part of the peptide chain of strand is usually translated simultaneously by such nuclear proteins and probably create a many ribosomes (polyribosomes or polysomes) peptide loop on the protein’s surface. In the at different sites, a protein is synthesized much case of the cytoplasmic receptor for glucocor- faster than its mRNA. In the bone marrow, for ticoids ( p. 278), the nuclear localization sig- example, a total of around 5 1014 hemoglobin nal is masked by a chaperone protein (heat copies containing 574 amino acids each are shock protein 90, hsp90) in the absence of the produced per second. glucocorticoid, and is released only after the The endoplasmic reticulum (ER, C, F) hormone binds, thereby freeing hsp90 from plays a central role in the synthesis of proteins the receptor. The “activated” receptor then and lipids; it also serves as an intracellular Ca2+ reaches the cell nucleus, where it binds to store ( p. 17 A). The ER consists of a net-like specific DNA sequences and controls specific system of interconnected branched channels genes. and flat cavities bounded by a membrane. The The nuclear envelope consists of two mem- enclosed spaces (cisterns) make up around 10% branes (= two phospholipid bilayers) that of the cell volume, and the membrane com- merge at the nuclear pores. The two mem- prises up to 70% of the membrane mass of a branes consist of different materials. The ex- cell. Ribosomes can attach to the cytosolic sur-10 ternal membrane is continuous with the mem- face of parts of the ER, forming a rough endo- Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 23. C. Transcription and translation Genomic DNA Nucleus Cytoplasm Nuclear pore RNA polymerase Transcription factors and signal RNA 5’ a 2 Translation in ribosomes Transcription Primary RNA mRNA Ribosome subunits 3’ b end Splicing The Cell II Stop tRNA mRNA amino acids c mRNA export Plate 1.5 d mRNA Growing Ribosomes Ribosome peptide chain breakdown tRNA amino acids1 Cytosolic Start Finished protein peptide chain e tRNA 5’ end Translation amino acids Ribosomes Membrane-bound and export proteins Control (cf. Plate F.) D. Transcription and splicing E. Protein coding in DNA and RNA Coding for amino acid no. ... 3’ 5’ 1–15 16 – 44 45 – 67 DNA T A A A A T G C T C T CGenomicDNA Codogen Transcription Transcription and Splicing 5’ 3’ Export from nucleusPrimary end Exon Intron endRNA(hnRNA) 5’ 3’ mRNA A U U U U A C G A G A G Codon Anti- 3’-poly-A tail Reading direction codon C U C A 5’ A A A A Ribosome cap tRNAGlu C 5’ C Splicing Introns Protein A A NH2 Ile Leu Arg Glu A A A AmRNA 11 1 15 44 67 Growth of peptide chainDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 24. plasmic reticulum (RER). These ribosomes syn- Hence, the Golgi apparatus represents a thesize export proteins as well as transmem- central modification, sorting and distribution brane proteins ( G) for the plasma mem- center for proteins and lipids received from the brane, endoplasmic reticulum, Golgi appara- endoplasmic reticulum. tus, lysosomes, etc. The start of protein synthe- Regulation of gene expression takes place sis (at the amino end) by such ribosomes (still on the level of transcription ( C1a), RNA unattached) induces a signal sequence to modification ( C1b), mRNA export ( C1c), which a signal recognition particle (SRP) in the RNA degradation ( C1d), translation ( C1e), cytosol attaches. As a result, (a) synthesis is modification and sorting ( F,f), and protein1 Fundamentals and Cell Physiology temporarily halted and (b) the ribosome (me- degradation ( F,g). diated by the SRP and a SRP receptor) attaches The mitochondria ( A, B; p. 17 B) are the to a ribosome receptor on the ER membrane. site of oxidation of carbohydrates and lipids to After that, synthesis continues. In export pro- CO2 and H2O and associated O2 expenditure. tein synthesis, a translocator protein conveys The Krebs cycle (citric acid cycle), respiratory the peptide chain to the cisternal space once chain and related ATP synthesis also occur in synthesis is completed. Synthesis of membrane mitochondria. Cells intensely active in meta- proteins is interrupted several times (depend- bolic and transport activities are rich in mito- ing on the number of membrane-spanning chondria—e.g., hepatocytes, intestinal cells, domains ( G2) by translocator protein clo- and renal epithelial cells. Mitochondria are en- sure, and the corresponding (hydrophobic) closed in a double membrane consisting of a peptide sequence is pushed into the phos- smooth outer membrane and an inner mem- pholipid membrane. The smooth endoplasmic brane. The latter is deeply infolded, forming a reticulum (SER) contains no ribosomes and is series of projections (cristae); it also has im- the production site of lipids (e.g., for lipo- portant transport functions ( p. 17 B). Mito- proteins, p. 254 ff.) and other substances. chondria probably evolved as a result of sym- The ER membrane containing the synthesized biosis between aerobic bacteria and anaerobic membrane proteins or export proteins forms cells (symbiosis hypothesis). The mitochondrial vesicles which are transported to the Golgi ap- DNA (mtDNA) of bacterial origin and the paratus. double membrane of mitochondria are relicts The Golgi complex or Golgi apparatus ( F) of their ancient history. Mitochondria also has sequentially linked functional compart- contain ribosomes which synthesize all pro- ments for further processing of products from teins encoded by mtDNA. the endoplasmic reticulum. It consists of a cis- Lysosomes are vesicles ( F) that arise from Golgi network (entry side facing the ER), the ER (via the Golgi apparatus) and are in- stacked flattened cisternae (Golgi stacks) and a volved in the intracellular digestion of macro- trans-Golgi network (sorting and distribution). molecules. These are taken up into the cell Functions of the Golgi complex: either by endocytosis (e.g., uptake of albumin ! polysaccharide synthesis; into the renal tubules; p. 158) or by phagocy- ! protein processing (posttranslational modi- tosis (e.g., uptake of bacteria by macrophages; fication), e.g., glycosylation of membrane pro- p. 94 ff.). They may also originate from the teins on certain amino acids (in part in the ER) degradation of a cell’s own organelles (auto- that are later borne as glycocalyces on the ex- phagia, e.g., of mitochondria) delivered inside ternal cell surface (see below) and γ-carboxy- autophagosomes ( B, F). A portion of the en- lation of glutamate residues ( p. 102 ); docytosed membrane material recycles (e.g., ! phosphorylation of sugars of glycoproteins receptor recycling in receptor-mediated en- (e.g., to mannose-6-phosphate, as described docytosis; p. 28). Early and late endosomes below); are intermediate stages in this vesicular trans- ! “packaging” of proteins meant for export port. Late endosomes and lysosomes contain into secretory vesicles (secretory granules), the acidic hydrolases (proteases, nucleases, li- contents of which are exocytosed into the ex- pases, glycosidases, phosphatases, etc., that12 tracellular space; see p. 246, for example. are active only under acidic conditions). The Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 25. F. Protein synthesis, sorting, recycling, and breakdown Nucleus Cytosol Transcription mRNA Free ribosomes Cytosolic ER-bound proteins ribosomes Protein and lipid synthesis The Cell III Mitochondrion Endoplasmatic reticulum (ER) Plate 1.6 cis-Golgi network Auto- Protein and lipid modification Golgi stacks phagosome Micro- tubule f g Sorting trans-Golgi Breakdown network of macro- Protein breakdown molecules M6P receptor Recycling Lysosome Secretory Late vesicle endosome Signal Early endosome Cytosol Phagocytosis Protein inclusion in cell membrane Extra- Recycling cellular of receptors space Clathrin Exocytose Endocytosis ControlledBacterium protein Constitutive secretion secretion 13 ControlDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 26. membrane contains an H+-ATPase that creates below. Cholesterol (present in both layers) re- an acidic (pH 5) interior environment within duces both the fluidity of the membrane and the lysosomes and assorted transport proteins its permeability to polar substances. Within that (a) release the products of digestion (e.g., the two-dimensionally fluid phospholipid amino acids) into the cytoplasm and (b) ensure membrane are proteins that make up 25% (my- charge compensation during H+ uptake (Cl– elin membrane) to 75% (inner mitochondrial channels). These enzymes and transport pro- membrane) of the membrane mass, depend- teins are delivered in primary lysosomes from ing on the membrane type. Many of them span the Golgi apparatus. Mannose-6-phosphate the entire lipid bilayer once ( G1) or several1 Fundamentals and Cell Physiology (M6 P) serves as the “label” for this process; it times ( G2) (transmembrane proteins), binds to M6 P receptors in the Golgi membrane thereby serving as ion channels, carrier pro- which, as in the case of receptor-mediated en- teins, hormone receptors, etc. The proteins are docytosis ( p. 28 ), cluster in the membrane anchored by their lipophilic amino acid resi- with the help of a clathrin framework. In the dues, or attached to already anchored proteins. acidic environment of the lysosomes, the Some proteins can move about freely within enzymes and transport proteins are separated the membrane, whereas others, like the anion from the receptor, and M6 P is dephosphory- exchanger of red cells, are anchored to the cy- lated. The M6 P receptor returns to the Golgi toskeleton. The cell surface is largely covered apparatus (recycling, F). The M6 P receptor by the glycocalyx, which consists of sugar no longer recognizes the dephosphorylated moieties of glycoproteins and glycolipids in proteins, which prevents them from returning the cell membrane ( G1,4) and of the extra- to the Golgi apparatus. cellular matrix. The glycocalyx mediates cell– Peroxisomes are microbodies containing cell interactions (surface recognition, cell enzymes (imported via a signal sequence) that docking, etc.). For example, components of the permit the oxidation of certain organic glycocalyx of neutrophils dock onto en- molecules (R-H2), such as amino acids and dothelial membrane proteins, called selectins fatty acids: R-H2 + O2 R + H2O2. The peroxi- ( p. 94). somes also contain catalase, which transforms The cytoskeleton allows the cell to maintain 2 H2O2 into O2 + H2O and oxidizes toxins, such and change its shape (during cell division, etc.), as alcohol and other substances. make selective movements (migration, cilia), Whereas the membrane of organelles is re- and conduct intracellular transport activities sponsible for intracellular compartmentaliza- (vesicle, mitosis). It contains actin filaments as tion, the main job of the cell membrane ( G) well as microtubules and intermediate fila- is to separate the cell interior from the extra- ments (e.g., vimentin and desmin filaments, cellular space ( p. 2). The cell membrane is a neurofilaments, keratin filaments) that extend phospholipid bilayer ( G1) that may be either from the centrosome. smooth or deeply infolded, like the brush border or the basal labyrinth ( B). Depending on the cell type, the cell membrane contains variable amounts of phospholipids, cholesterol, and glycolipids (e.g., cerebrosides). The phos- pholipids mainly consist of phosphatidylcho- line ( G3), phosphatidylserine, phosphati- dylethanolamine, and sphingomyelin. The hy- drophobic components of the membrane face each other, whereas the hydrophilic com- ponents face the watery surroundings, that is, the extracellular fluid or cytosol ( G4). The lipid composition of the two layers of the membrane differs greatly. Glycolipids are14 present only in the external layer, as described Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 27. G. Cell membrane Extracellular Integral Lipid molecule membrane protein Glycoprotein Glycolipid Glycocalyx Lipid bilayer (ca. 5 nm) The Cell IV Plate 1.7 Cytosol Peripheral membrane protein 1 Membrane constituents Lipophilic amino acid residues 2 Multiple membrane- Glycolipid spanning integral protein Cholesterol Choline Polar head group (hydrophilic) Glycerol Double bond Fatty acids (hydrophobic) Phosphatidylserine 3 Phospholipid (phosphatidylcholine) 15 4 Membrane lipidsDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 28. ! Endoplasmic reticulum (ER): In addition to a Transport In, Through and Between translocator protein ( p. 10), the ER has two Cells other proteins that transport Ca2+ ( A). Ca2+ The lipophilic cell membrane protects the cell can be pumped from the cytosol into the ER by interior from the extracellular fluid, which has a Ca2+-ATPase called SERCA (sarcoplasmic en- a completely different composition ( p. 2). doplasmic reticulum Ca2+-transporting This is imperative for the creation and main- ATPase). The resulting Ca2+ stores can be re- tenance of a cell’s internal environment by leased into the cytosol via a Ca2+ channel (ry- means of metabolic energy expenditure. Chan- anodine receptor, RyR) in response to a trigger-1 Fundamentals and Cell Physiology nels (pores), carriers, ion pumps ( p. 26ff.) ing signal ( p. 36). and the process of cytosis ( p. 28) allow ! Mitochondria: The outer membrane con- transmembrane transport of selected sub- tains large pores called porins that render it stances. This includes the import and export of permeable to small molecules ( 5 kDa), and metabolic substrates and metabolites and the the inner membrane has high concentrations selective transport of ions used to create or of specific carriers and enzymes ( B). modify the cell potential ( p. 32), which plays Enzyme complexes of the respiratory chain an essential role in excitability of nerve and transfer electrons (e–) from high to low energy muscle cells. In addition, the effects of sub- levels, thereby pumping H+ ions from the stances that readily penetrate the cell mem- matrix space into the intermembrane space brane in most cases (e.g., water and CO2) can be ( B1), resulting in the formation of an H+ ion mitigated by selectively transporting certain gradient directed into the matrix. This not only other substances. This allows the cell to com- drives ATP synthetase (ATP production; B2), pensate for undesirable changes in the cell but also promotes the inflow of pyruvate – and volume or pH of the cell interior. anorganic phosphate, Pi– (symport; B2b,c and p. 28). Ca2+ ions that regulate Ca2+-sensi- Intracellular Transport tive mitochondrial enzymes in muscle tissue The cell interior is divided into different com- can be pumped into the matrix space with ATP partments by the organelle membranes. In expenditure ( B2), thereby allowing the mi- some cases, very broad intracellular spaces tochondria to form a sort of Ca2+ buffer space must be crossed during transport. For this pur- for protection against dangerously high con- pose, a variety of specific intracellular trans- centrations of Ca2+ in the cytosol. The inside- port mechanisms exist, for example: negative membrane potential (caused by H+ re- ! Nuclear pores in the nuclear envelope pro- lease) drives the uptake of ADP3 – in exchange vide the channels for RNA export out of the nu- for ATP4 – (potential-driven transport; B2a cleus and protein import into it ( p. 11 C); and p. 22). ! Protein transport from the rough endo- plasmic reticulum to the Golgi complex Transport between Adjacent Cells ( p. 13 F); In the body, transport between adjacent cells ! Axonal transport in the nerve fibers, in occurs either via diffusion through the extra- which distances of up to 1 meter can be cellular space (e.g., paracrine hormone effects) crossed ( p. 42). These transport processes or through channel-like connecting structures mainly take place along the filaments of the (connexons) located within a so-called gap cytoskeleton. Example: while expending ATP, junction or nexus ( C). A connexon is a hemi- the microtubules set dynein-bound vesicles in channel formed by six connexin molecules motion in the one direction, and kinesin- ( C2). One connexon docks with another con- bound vesicles in the other ( p. 13 F). nexon on an adjacent cell, thereby forming a common channel through which substances Intracellular Transmembrane Transport with molecular masses of up to around 1 kDa Main sites: can pass. Since this applies not only for ions ! Lysosomes: Uptake of H+ ions from the cyto- such as Ca2+, but also for a number of organic16 sol and release of metabolites such as amino substances such as ATP, these types of cells are acids into the cytosol ( p. 12); Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 29. A. Ca2+ transport through the ER membrane Transport In, Through and Between Cells I Nucleus 1 2 Cytosol Ca2+ Endoplasmic Ca2+ channel Ca2+-ATPase reticulum (ER) Signal (depolarization, hormon, etc.) Discharge Ca2+ Storage Cytosolic (10–5) 10–8 mol/l 10–5 (10–8)mol/l Ca2+ concentration B. Mitochondrial transport Plate 1.8 Outer membrane Inner membrane Matrix ATP synthetase Crista Inter- Ribosomes membranous space Granules Cytosol 1 Formation of H+ gradient 2 H+ gradient driving ATP synthesis and carriers NADH + H+ H2 O Pyruvate– NAD+ Pi + ADP3– etc. synthetase + 2H + ½O2 H+ Pi ADP3– ATP Carrier Matrix ATP 4– e– a b c Enzyme complexes H+ of respiratory chain H+ ATP H+ H+ H+ H+ Intermembranous H+ ATP 4– H+ H + 2+ Ca space H+ Cytoplasm Porins 17Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 30. united to form a close electrical and metabolic their structure ( p. 9A and B) and transport unit (syncytium), as is present in the function. Hence, the apical membrane (facing epithelium, many smooth muscles (single- exterior) of an epithelial cell has a different set unit type, p. 70), the myocardium, and the of transport proteins from the basolateral glia of the central nervous system. Electric membrane (facing the blood). Tight junctions coupling permits the transfer of excitation, (described below) at which the outer phos- e.g., from excited muscle cells to their adjacent pholipid layer of the membrane folds over, cells, making it possible to trigger a wave of ex- prevent lateral mixing of the two membranes citation across wide regions of an organ, such ( D2).1 Fundamentals and Cell Physiology as the stomach, intestine, biliary tract, uterus, Whereas the apical and basolateral mem- ureter, atrium, and ventricles of the heart. Cer- branes permit transcellular transport, para- tain neurons of the retina and CNS also com- cellular transport takes place between cells. municate in this manner (electric synapses). Certain epithelia (e.g., in the small intestinal Gap junctions in the glia ( p. 338) and and proximal renal tubules) are relatively per- epithelia help to distribute the stresses that meable to small molecules (leaky), whereas occur in the course of transport and barrier ac- others are less leaky (e.g., distal nephron, tivities (see below) throughout the entire cell colon). The degree of permeability depends on community. However, the connexons close the strength of the tight junctions (zonulae when the concentration of Ca2+ (in an extreme occludentes) holding the cells together ( D). case, due to a hole in cell membrane) or H+ The paracellular pathway and the extent of its concentration increases too rapidly ( C3). In permeability (sometimes cation-specific) are other words, the individual (defective) cell is essential functional elements of the various left to deal with its own problems when neces- epithelia. Macromolecules can cross the bar- sary to preserve the functionality of the cell rier formed by the endothelium of the vessel community. wall by transcytosis ( p. 28), yet paracellular transport also plays an essential role, es- Transport through Cell Layers pecially in the fenestrated endothelium. Multicellular organisms have cell layers that Anionic macromolecules like albumin, which are responsible for separating the “interior” must remain in the bloodstream because of its from the “exterior” of the organism and its colloid osmotic action ( p. 208), are held back larger compartments. The epithelia of skin and by the wall charges at the intercellular spaces gastrointestinal, urogenital and respiratory and, in some cases, at the fenestra. tracts, the endothelia of blood vessels, and neu- Long-distance transport between the roglia are examples of this type of extensive various organs of the body and between the barrier. They separate the immediate extra- body and the outside world is also necessary. cellular space from other spaces that are Convection is the most important transport greatly different in composition, e.g., those mechanism involved in long-distance trans- filled with air (skin, bronchial epithelia), port ( p. 24). gastrointestinal contents, urine or bile (tubules, urinary bladder, gallbladder), aqueous humor of the eye, blood (endothelia) and cerebrospinal fluid (blood–cerebrospinal fluid barrier), and from the extracellular space of the CNS (blood–brain barrier). Nonetheless, certain substances must be able to pass through these cell layers. This requires selec- tive transcellular transport with import into the cell followed by export from the cell. Un- like cells with a completely uniform plasma membrane (e.g., blood cells), epi- and en-18 dothelial cells are polar cells, as defined by Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 31. C. Gap junction Transport In, Through and Between Cells II Cell 1 COO– Channel (1.2–1.5 nm) NH3+ Cytosol 1 Cell 2 Cell membranes Cytosol 2 1 Ions, ATP, cAMP, amino acids, etc. Connexon of Cell 1 3 2 Plate 1.9 Connexin (27 kDa) Connexon of Cell 2 Channel open Channel closed D. Apical functional complex Apical Microvilli 1 Tight Para- junction cellular transport See (2) Cell 2 Actin- myosin Zonula Cell 1 belt adherens Epithelial cells (e.g., enterocytes) Basolateral N N Occlusin E-cadherin Myosin II Actin Adapter proteins Ca2+ 2 19 Photos: H. Lodish. Reproduced with permission from Scientific American Books, New York, 1995.Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 32. dC Passive Transport by Means of Jdiff A!D! [mol ! s–1] [1.2] dx Diffusion where C is the molar concentration and x is the Diffusion is movement of a substance owing to distance traveled during diffusion. Since the the random thermal motion (brownian move- driving “force”—i.e., the concentration gradient ment) of its molecules or ions ( A1) in all (dC/dx)—decreases with distance, as was ex- directions throughout a solvent. Net diffusion plained above, the time required for diffusion or selective transport can occur only when the increases exponentially with the distance1 Fundamentals and Cell Physiology solute concentration at the starting point is traveled (t x2). If, for example, a molecule higher than at the target site. (Note: uni- travels the first µm in 0.5 ms, it will require 5 s directional fluxes also occur in absence of a to travel 100 µm and a whopping 14 h for 1 cm. concentration gradient—i.e., at equilibrium— Returning to the previous example ( A2), but net diffusion is zero because there is equal if the above-water partial pressure of free O2 flux in both directions.) The driving force of diffusion ( A2) is kept constant, the Po2 in the diffusion is, therefore, a concentration gra- water and overlying gas layer will eventually dient. Hence, diffusion equalizes concentra- equalize and net diffusion will cease (diffusion tion differences and requires a driving force: equilibrium). This process takes place within passive transport (= downhill transport). the body, for example, when O2 diffuses from Example: When a layer of O2 gas is placed the alveoli of the lungs into the bloodstream on water, the O2 quickly diffuses into the water and when CO2 diffuses in the opposite direc- along the initially high gas pressure gradient tion ( p. 120). ( A2). As a result, the partial pressure of O2 Let us imagine two spaces, a and b ( B1) (Po2) rises, and O2 can diffuse further containing different concentrations (Ca Cb) downward into the next O2-poor layer of water of an uncharged solute. The membrane sepa- ( A1). (Note: with gases, partial pressure is rating the solutions has pores ∆x in length and used in lieu of concentration.) However, the with total cross-sectional area of A. Since the steepness of the Po2 profile or gradient (dPo2/ pores are permeable to the molecules of the dx) decreases (exponentially) in each sub- dissolved substance, the molecules will diffuse sequent layer situated at distance x from the from a to b, with Ca – Cb = ∆C representing the O2 source ( A3). Therefore, diffusion is only concentration gradient. If we consider only the feasible for transport across short distances spaces a and b (while ignoring the gradients within the body. Diffusion in liquids is slower dC/dx in the pore, as shown in B2, for the sake than in gases. of simplicity), Fick’s first law of diffusion The diffusion rate, Jdiff (mol · s–1), is the (Eq. 1.2) can be modified as follows: amount of substance that diffuses per unit of ∆C time. It is proportional to the area available for Jdiff A!D! [mol ! s–1]. [1.3] ∆x diffusion (A) and the absolute temperature (T) and is inversely proportional to the viscosity In other words, the rate of diffusion increases (η) of the solvent and the radius (r) of the dif- as A, D, and ∆C increase, and decreases as the fused particles. thickness of the membrane (∆x) decreases. According to the Stokes–Einstein equation, When diffusion occurs through the lipid the coefficient of diffusion (D) is derived from T, membrane of a cell, one must consider that hy- η, and r as drophilic substances in the membrane are sparingly soluble (compare intramembrane R!T D [m2 ! s–1], [1.1] gradient in C1 to C2) and, accordingly, have a N A · 6π ! r ! η hard time penetrating the membrane by where R is the general gas constant means of “simple” diffusion. The oil-and-water (8.3144 J · K–1 · mol–1) and NA Avogadro’s con- partition coefficient (k) is a measure of the lipid stant (6.022 · 1023 mol–1). In Fick’s first law of solubility of a substance ( C). diffusion (Adolf Fick, 1855), the diffusion rate20 is expressed as Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 33. A. Diffusion in homogeneous media Passive Transport by Means of Diffusion I1 Brownian particle movement (~T) 2 Passive transport 3 PO2 profile Gas O2 PO2 O2 O2 O2 PO2 0 Slope=gradient P = dP/dx X PO2 x Water P x 0 Distance from O2 source (x) B. Diffusion through porous membranes 1 2 Plate 1.10 Porous membrane Space a Space b Ca Gradient Cb Pore Cb a C Space a Membrane Space b ∆x Ca – Cb =∆C C. Diffusion through lipid membranes 1 2 5 nm Hydrophilic Hydrophobic substance X substance Y (k <1) (k >1) CXa Gradient CY a Gradient b CX CY b Lipid Lipid Water membrane Water Water membrane Water Equilibrium concentration in olive oil k= Equilibrium concentration in water 21 (Partly after S. G. Schultz)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 34. The higher the k value, the more quickly the sub- ( p. 176 ff.). Since the pH of a solution deter- stance will diffuse through a pure phospholipid mines whether these substances will be bilayer membrane. Substitution into Eq. 1.3 gives charged or not (pK value; p. 378), the diffu- ∆C sion of weak acids and bases is clearly depend- Jdiff k!A!D! [mol ! s–1]; [1.4] ∆x ent on the pH. The previous equations have not made al- Whereas the molecular radius r ( Eq. 1.1) still lowances for the diffusion of electrically largely determines the magnitude of D when k re- charged particles (ions). In their case, the elec- mains constant (cf. diethylmalonamide with ethyl- trical potential difference at cell membranes1 Fundamentals and Cell Physiology urea in D), k can vary by many powers of ten when r remains constant (cf. urea with ethanol in D) and can must also be taken into account. The electrical therefore have a decisive effect on the permeability potential difference can be a driving force of of the membrane. diffusion (electrodiffusion). In that case, posi- tively charged ions (cations) will then migrate Since the value of the variables k, D, and ∆x to the negatively charged side of the mem- within the body generally cannot be deter- brane, and negatively charged ions (anions) mined, they are usually summarized as the will migrate to the positively charged side. The permeability coefficient P, where prerequisite for this type of transport is, of D course, that the membrane contain ion chan- P k! [m ! s–1]. [1.5] ∆x nels ( p. 32 ff.) that make it permeable to the transported ions. Inversely, every ion diffusing If the diffusion rate, Jdiff [mol!s – 1], is related to along a concentration gradient carries a charge area A, Eq. 1.4 is transformed to yield and thus creates an electric diffusion potential Jdiff ( p. 32 ff.). P ! ∆C [mol ! m–2 ! s–1]. [1.6] A As a result of the electrical charge of an ion, the per- The quantity of substance (net) diffused per meability coefficient of the ion x (= Px) can be trans- unit area and time is therefore proportional to formed into the electrical conductance of the ∆C and P ( E, blue line with slope P). membrane for this ion, gx ( p. 32): When considering the diffusion of gases, ∆C gx ! Px ! zx2 ! F2 R–1 ! T–1 ! cx [S ! m–2] [1.9] in Eq. 1.4 is replaced by α· ∆P (solubility coeffi- cient times partial pressure difference; where R and T have their usual meaning (explained . above) and zx equals the charge of the ion, F equals p. 126) and Jdiff [mol ! s–1] by Vdiff [m3! s–1]. k · α · D is then summarized as diffusion con- the Faraday constant (9,65 ! 104 A ! s ! mol–1), and cx equals the mean ionic activity in the membrane. ductance, or Krogh’s diffusion coefficient K [m2 ! Furthermore, s–1 ! Pa–1]. Substitution into Fick’s first diffusion equation yields c1 – c2 c . [1.10] . lnc1 – lnc2 Vdiff ∆P K! [m ! s–1]. [1.7] where index 1 = one side and index 2 = the other side A ∆x of the membrane. Unlike P, g is concentration-depend- Since A and ∆x of alveolar gas exchange ent. If, for example, the extracellular K+ concentration ( p. 120) cannot be determined in living or- rises from 4 to 8 mmol/kg H2O (cytosolic concentra- ganisms, K · F/∆x for O2 is often expressed as tion remains constant at 160 mmol/kg H2O), c will the O2 diffusion capacity of the lung, DL: rise, and g will increase by 20%. . Since most of the biologically important VO2 diff DL ! ∆PO2 [m3 ! s–1]. [1.8] substances are so polar or lipophobic (small Nonionic diffusion occurs when the uncharged k value) that simple diffusion of the substances form of a weak base (e.g., ammonia = NH3) or through the membrane would proceed much acid (e.g., formic acid, HCOOH) passes through too slowly, other membrane transport proteins a membrane more readily than the charged called carriers or transporters exist in addition form ( F). In this case, the membrane would to ion channels. Carriers bind the target22 be more permeable to NH3 than to NH4+ molecule (e.g., glucose) on one side of the membrane and detach from it on the other side Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 35. D. Permeability of lipid membranes E. Facilitated diffusion 3•10–5 Methanol Triethyl Passive Transport by Means of Diffusion II citrate Ethanol Facilitated diffusion Trimethyl citrate (see G. for carriers) Permeability coefficient (m•s–1) Antipyrine Valeramide Transport rate [mol•m–2• s–1] Cyanamide on 3•10–6 Diacetin ati Butyramide ur Acetamide Chlorohydrin Sat (Data from Collander et al.) Ethylene Succinamide glycol Dimethylurea Ethylurea 3•10–7 Methyl- urea Diethylmalonamide Urea (Sphere diameter Simple diffusion 3•10–8 = molecular radius) Glycerol 10–4 10–3 10–2 10–1 1 ∆C[mol• m–3] Distribution coefficient k for olive oil/water F. Nonionic diffusion G. Passive carrier transport Carrier Plate 1.11 H+ + NH4+ protein NH4+ + H + NH3 NH3 H+ + HCOO– HCOO– + H+ HCOOH HCOOH(after a conformational change) ( G). As in ration and is specific for structurally similarsimple diffusion, a concentration gradient is substances that may competitively inhibit onenecessary for such carrier-mediated transport another. The carriers in both passive and active(passive transport), e.g., with GLUT uniporters transport have the latter features in commonfor glucose ( p. 158). On the other hand, this ( p. 26).type of “facilitated diffusion” is subject to satu- 23 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 36. Osmosis, Filtration and Convection In filtration ( B), Water flow or volume flow (JV) across a mem- JV Kf ! ∆P – ∆π [1.13] brane, in living organisms is achieved through Filtration occurs through capillary walls, osmosis (diffusion of water) or filtration. They which allow the passage of small ions and can occur only if the membrane is water-per- molecules (σ = 0; see below), but not of plasma meable. This allows osmotic and hydrostatic proteins ( B, molecule x). Their concentra- pressure differences (∆π and ∆P) across the tion difference leads to an oncotic pressure membrane to drive the fluids through it. difference (∆π) that opposes ∆P. Therefore, fil- Osmotic flow equals the hydraulic conduc- tration can occur only if ∆P ∆π ( B, p. 152,1 Fundamentals and Cell Physiology tivity (Kf) times the osmotic pressure differ- p. 208). ence (∆π) ( A): Solvent drag occurs when solute particles JV Kf ! ∆π [1.11] are carried along with the water flow of osmo- The osmotic pressure difference (∆π) can be sis or filtration. The amount of solvent drag for calculated using van’t Hoff’s law, as modified solute X (JX) depends mainly on osmotic flow by Staverman: (JV) and the mean solute activity ax ( p. 376) ∆π σ ! R ! T ! ∆Cosm, [1.12] at the site of penetration, but also on the where σ is the reflection coefficient of the par- degree of particle reflection from the mem- ticles (see below), R is the universal gas con- brane, which is described using the reflection stant ( p. 20), T is the absolute temperature, coefficient (σ). Solvent drag for solute X (JX) is and ∆Cosm [osm ! kgH2O–1] is the difference be- therefore calculated as tween the lower and higher particle concen- Jx JV (1 – σ) ax [mol ! s–1] [1.14] trations, Ca – Cb osm osm ( A). Since ∆Cosm, the Larger molecules such as proteins are entirely driving force for osmosis, is a negative value, JV reflected, and σ = 1 ( B, molecule X). Reflec- is also negative (Eq. 1.11). The water therefore tion of smaller molecules is lower, and σ 1. flows against the concentration gradient of the When urea passes through the wall of the solute particles. In other words, the higher proximal renal tubule, for example, σ = concentration, Cb , attracts the water. When osm 0.68. The value (1–σ) is also called the sieving the concentration of water is considered in os- coefficient ( p. 154). mosis, the H2O concentration in A,a, Ca 2O, is H Plasma protein binding occurs when small- greater than that in A,b, Cb 2O. CaH2O – Cb 2O is H H molecular substances in plasma bind to pro- therefore the driving force for H2O diffusion teins ( C). This hinders the free penetration ( A). Osmosis also cannot occur unless the of the substances through the endothelium or reflection coefficient is greater than zero the glomerular filter ( p. 154 ff.). At a glo- (σ 0), that is, unless the membrane is less merular filtration fraction of 20%, 20% of a permeable to the solutes than to water. freely filterable substance is filtered out. If, Aquaporins (AQP) are water channels that however, 9/10 of the substance is bound to permit the passage of water in many cell mem- plasma proteins, only 2% will be filtered during branes. A chief cell in the renal collecting duct each renal pass. contains a total of ca. 107 water channels, com- Convection functions to transport solutes prising AQP2 (regulated) in the luminal mem- over long distances—e.g., in the circulation or brane, and AQP3 and 4 (permanent?) in the ba- urinary tract. The solute is then carried along solateral membrane. The permeability of the like a piece of driftwood. The quantity of solute epithelium of the renal collecting duct to transported over time (Jconv) is the product of water ( A, right panel) is controlled by the in- volume flow JV (in m3 ! s–1) and the solute con- sertion and removal of AQP2, which is stored in centration C (mol ! m–3): the membrane of intracellular vesicles. In the Jconv JV ! C [mol ! s–1]. [1.15] presence of the antidiuretic hormone ADH (V2 The flow of gases in the respiratory tract, the receptors, cAMP; p. 274), water channels transmission of heat in the blood and the re- are inserted in the luminal membrane within lease of heat in the form of warmed air occurs minutes, thereby increasing the water perme- through convection ( p. 222).24 ability of the membrane to around 1.5 10– 17 L s– 1 per channel. Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 37. A. Osmosis (water diffusion) ∆π Example Cbosm Lumen Interstice Caosm CbH2OCaH2O H2O Osmosis, Filtration and Convection Cbosm > Caosm , Aqua- porins i.e., H 2O CaH2O > CbH2O a b Water diffusion from a to b Epithelium of renal collecting duct Water flux JV = Kf · ∆π (~ Caosm – Cbosm) B. Filtration ∆P Example Pa Pb Glomerular Plate 1.12 capillary Pa > P b and ∆P > ∆πx x a b Blood Water filtration from a to b ∆ πx ∆P ∆π Water flux JV = Kf · (∆P – ∆πx) Primary Filtrate (= oncotic pressure of plasma proteins) urine C. Plasma protein binding Prevents excretion (e.g., binding of heme by hemopexin)Protein Blood side Transports substances in blood (e.g., binding of Fe3+ ions by apotransferrin) Provides rapid access ion stores (e. g., of Ca2+ or Mg2+) Helps to dissolve lipophilic substances in blood (e.g., unconjugated bilirubin) a b Affects certain medications (e.g., many sulfonamides): H2 O Protein-bound fraction – not pharmacologically active – not filtratable (delays renal excretion) 25 – functions as an allergen (hapten)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 38. and, thus, for maintenance of the cell mem- Active Transport brane potential. During each transport cycle Active transport occurs in many parts of the ( A1, A2), 3 Na+ and 2 K+ are “pumped” out of body when solutes are transported against and into the cell, respectively, while 1 ATP their concentration gradient (uphill transport) molecule is used to phosphorylate the carrier and/or, in the case of ions, against an electrical protein ( A2b). Phosphorylation first potential ( p. 22). All in all, active transport changes the conformation of the protein and occurs against the electrochemical gradient or subsequently alters the affinities of the Na+ potential of the solute. Since passive transport and K+ binding sites. The conformational1 Fundamentals and Cell Physiology mechanisms represent “downhill” transport change is the actual ion transport step since it ( p. 20 ff.), they are not appropriate for this moves the binding sites to the opposite side of task. Active transport requires the expenditure the membrane ( A2b – d). Dephosphoryla- of energy. A large portion of chemical energy tion restores the pump to its original state provided by foodstuffs is utilized for active ( A2e – f). The Na+/K+ pumping rate increases transport once it has been made readily avail- when the cytosolic Na+ concentration rises— able in the form of ATP ( p. 41). The energy due, for instance, to increased Na+ influx, or created by ATP hydrolysis is used to drive the when the extracellular K+ rises. Therefore, transmembrane transport of numerous ions, Na+,K+-activatable ATPase is the full name of metabolites, and waste products. According to the pump. Na-+K+-ATPase is inhibited by the laws of thermodynamics, the energy ex- ouabain and cardiac glycosides. pended in these reactions produces order in Secondary active transport occurs when cells and organelles—a prerequisite for sur- uphill transport of a compound (e.g., glucose) vival and normal function of cells and, there- via a carrier protein (e.g., sodium glucose fore, for the whole organism ( p. 38 ff.). transporter type 2, SGLT2) is coupled with the In primary active transport, the energy pro- passive (downhill) transport of an ion (in this duced by hydrolysis of ATP goes directly into example Na+; B1). In this case, the electro- ion transport through an ion pump. This type chemical Na+ gradient into the cell (created by of ion pump is called an ATPase. They establish Na+-K+-ATPase at another site on the cell mem- the electrochemical gradients rather slowly, brane; A) provides the driving force needed e.g., at a rate of around 1 µmol ! s–1 ! m–2 of for secondary active uptake of glucose into the membrane surface area in the case of Na+-K+- cell. Coupling of the transport of two com- ATPase. The gradient can be exploited to pounds across a membrane is called cotrans- achieve rapid ionic currents in the opposite port, which may be in the form of symport or direction after the permeability of ion chan- antiport. Symport occurs when the two com- nels has been increased ( p. 32 ff.). Na+ can, pounds (i.e., compound and driving ion) are for example, be driven into a nerve cell at a rate transported across the membrane in the same of up to 1000 µmol ! s–1 ! m–2 during an action direction ( B1–3). Antiport (countertrans- potential. port) occurs when they are transported in op- ATPases occur ubiquitously in cell mem- posite directions. Antiport occurs, for example, branes (Na+-K+-ATPase) and in the endo- when an electrochemical Na+ gradient drives plasmic reticulum and plasma membrane H+ in the opposite direction by secondary ac- (Ca2+-ATPase), renal collecting duct and stom- tive transport ( B4). The resulting H+ gradient ach glands (H+,K+ -ATPase), and in lysosomes can then be exploited for tertiary active sym- (H+-ATPase). They transport Na+, K+, Ca2+ and port of molecules such as peptides ( B5). H+, respectively, by primarily active mecha- Electroneutral transport occurs when the nisms. All except H+-ATPase consist of 2 α-sub- net electrical charge remains balanced during units and 2 β-subunits (P-type ATPases). The transport, e.g., during Na+/H+ antiport ( B4) α-subunits are phosphorylated and form the and Na+-Cl– symport ( B2). Small charge sep- ion transport channel ( A1). aration occurs in electrogenic (rheogenic) Na+-K+-ATPase is responsible for main- transport, e.g., in Na+-glucose0 symport26 tenance of intracellular Na+ and K+ homeostasis ( B1), Na+-amino acid0 symport ( B3), Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 39. A. Na+, K+-ATPase 3 Na+ 1 [Na+]o Outside [K+]o β β Cell membrane α α Active Transport I ADP [K+]i Cytosol [Na+]i ATP 2 K+ Plate 1.13 2 a b P ATP Na+ binding, Phosphorylation K+ discharge Confor- mational High affinity change for K+ c Conformation E1 f Na+ K+ P Conformation E2 hochaffin Na+ d Conformational change e P Na+ discharge, Pi K+ binding 27 Dephosphorylation (Partly after P. Läuger)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 40. 2 Na+-amino acid– symport, or H+-peptide0 sis) in conjunction with the expenditure of symport ( B5). The chemical Na+ gradient ATP. In cytosis, the uptake and release of mac- provides the sole driving force for elec- romolecules such as proteins, lipoproteins, troneutral transport (e.g., Na+/H+ antiport), polynucleotides, and polysaccharides into and whereas the negative membrane potential out of a cell occurs by specific mechanisms ( p. 32 ff.) provides an additional driving similar to those involved in intracellular trans- force for electrogenication–coupled cotrans- port ( p. 12 ff.). port into the cell. When secondary active Endocytosis ( p. 13) can be broken down transport (e.g., of glucose) is coupled with the into different types, including pinocytosis, re-1 Fundamentals and Cell Physiology influx of not one but two Na+ ions (e.g., SGLT1 ceptor-mediated endocytosis, and phagocyto- symporter), the driving force is doubled. The sis. Pinocytosis is characterized by the con- aid of ATPases is necessary, however, if the re- tinuous unspecific uptake of extracellular fluid quired “uphill” concentration ratio is several and molecules dissolved in it through rela- decimal powers large, e.g., 106 in the extreme tively small vesicles. Receptor-mediated en- case of H+ ions across the luminal membrane of docytosis ( C) involves the selective uptake parietal cells in the stomach. ATPase-mediated of specific macromolecules with the aid of re- transport can also be electrogenic or elec- ceptors. This usually begins at small depres- troneutral, e.g., Na+-K+-ATPase (3 Na+/2 K+; cf. sions (pits) on the plasma membrane surface. p. 46) or H+/K+-ATPase (1 H+/1 K+), respectively. Since the insides of the pits are often densely Characteristics of active transport: covered with the protein clathrin, they are ! It can be saturated, i.e., it has a limited maxi- called clathrin-coated pits. The receptors in- mum capacity (Jmax). volved are integral cell membrane proteins ! It is more or less specific, i.e., a carrier such as those for low-density lipoprotein (LPL; molecule will transport only certain chemi- e.g., in hepatocytes) or intrinsic factor-bound cally similar substances which inhibit the cobalamin (e.g., in ileal epithelial cells). Thou- transport of each other (competitive inhibi- sands of the same receptor type or of different tion). receptors can converge at coated pits ( C), ! Variable quantities of the similar substances yielding a tremendous increase in the efficacy are transported at a given concentration, i.e., of ligand uptake. The endocytosed vesicles are each has a different affinity (~1/KM) to the initially coated with clathrin, which is later re- transport system. leased. The vesicles then transform into early ! Active transport is inhibited when the endosomes, and most of the associated recep- energy supply to the cell is disrupted. tors circulate back to the cell membrane ( C All of these characteristics except the last and p. 13). The endocytosed ligand is either apply to passive carriers, that is, to uniporter- exocytosed on the opposite side of the cell mediated (facilitated) diffusion ( p. 22). (transcytosis, see below), or is digested by lyso- The transport rate of saturable transport somes ( C and p. 13). Phagocytosis involves (Jsat) is usually calculated according to Mi- the endocytosis of particulate matter, such as chaelis–Menten kinetics: microorganisms or cell debris, by phagocytes C ( p. 94 ff.) in conjunction with lysosomes. Jsat Jmax ! [1.16] KM + C Small digestion products, such as amino acids, where C is the concentration of the substrate in sugars and nucleotides, are transported out of question, Jmax is its maximum transport rate, the lysosomes into the cytosol, where they can and KM is the substrate concentration that pro- be used for cellular metabolism or secreted duces one-half Jmax ( p. 383). into the extracellular fluid. When certain hor- Cytosis is a completely different type of ac- mones such as insulin ( p. 282) bind to re- tive transport involving the formation of mem- ceptors on the surface of target cells, hormone- brane-bound vesicles with a diameter of receptor complexes can also enter the coated 50–400 nm. Vesicles are either pinched off pits and are endocytosed (internalized) and from the plasma membrane (exocytosis) or in- digested by lysosomes. This reduces the den-28 corporated into it by invagination (endocyto- sity of receptors available for hormone bind- Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 41. B. Secondary and tertiary active transport 1 Electrochemical Na+ gradient drives secondary active glucose transport Na+ Glucose [Na+]o Outside [Glucose] o + + Cell membrane Active Transport II – – Cytosol [Na+] i [Glucose]i 2 Electroneutral 3 Electrogenic 4 Electroneutral 5 Tertiary active symport symport antiport symport (electrogenic) Plate 1.14 [Na+]o [H+]o H+Cell membrane Outside + + – –Cytosol Cl– Na+ [Na+] i Amino Na+ Na+ [H+] i H+ Peptides acids C. Receptor-mediated endocytosis Coated pit Ligand Recycling of receptor Receptor and membrane Clathrin Endocytosis H+ H+ ATP ADP ATP Lysosomal degradation 29 Early endosome of ligandDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 42. ing. In other words, an increased hormone speeds of up to around 2000 µm/min. Other supply down-regulates the receptor density. cells also migrate, but at much slower rates. Fi- Exocytosis ( p. 13) is a method for selec- broblasts, for example, move at a rate of around tive export of macromolecules out of the cell 1.2 µm/min. When an injury occurs, fibroblasts (e.g., pancreatic enzymes; p. 246 ff.) and for migrate to the wound and aid in the formation release of many hormones (e.g., posterior of scar tissue. Cell migration also plays a role in pituitary hormone; p. 280) or neu- embryonal development. Chemotactically at- rotransmitters ( p. 50 ff.). These substances tracted neutrophil granulocytes and macro- are kept “packed” and readily available in phages can even migrate through vessel walls1 Fundamentals and Cell Physiology (clathrin-coated) secretory vesicles, waiting to to attack invading bacteria ( p. 94ff.). Cells of be released when a certain signal is received some tumors can also migrate to various tis- (increase in cytosolic Ca2+). The “packing mate- sues of the body or metastasize, thereby rial” (vesicle membrane) is later re-endocy- spreading their harmful effects. tosed and recycled. Exocytotic membrane fu- Cells migrate by “crawling” on a stable sur- sion also helps to insert vesicle-bound pro- face ( E1). The following activities occur teins into the plasma membrane ( p. 13).The during cell migration: liquid contents of the vesicle then are auto- ! Back end of the cell: (a) Depolymerization of matically emptied in a process called constitu- actin and tubulin in the cytoskeleton; (b) en- tive exocytosis ( D). docytosis of parts of the cell membrane, which are then propelled forward as endocytotic ves- In constitutive exocytosis, the protein complex coatomer (coat assembly protomer) takes on the role icles to the front of the cell, and (c) release of of clathrin (see above). Within the Golgi membrane, ions and fluids from the cell. GNRP (guanine nucleotide-releasing protein) ! Front end of the cell (lamellipodia): (a) Po- phosphorylates the GDP of the ADP-ribosylation fac- lymerization of actin monomers is achieved tor (ARF) to GTP D1), resulting in the dispatch of with the aid of profilin ( E2). The monomers vesicles from the trans-Golgi network. ARF-GTP are propelled forward with the help of plasma complexes then anchor on the membrane and bind membrane-based myosin I (fueled by ATP); with coatomer ( D2), thereby producing (b) reinsertion of the vesicles in the cell mem- coatomer-coated vesicles ( D3). The membranes of the vesicles contain v-SNAREs (vesicle synapto- brane; (c) uptake of ions and fluids from the some-associated protein receptors), which recognize environment. t-SNAREs (target-SNAREs) in the target membrane Parts of the cell membrane that are not in- (the plasma membrane, in this case). This results in volved in cytosis are conveyed from front to cleavage of ARF-GTP, dissociation of ARF-GDP and back, as on a track chain. Since the cell mem- coatomer molecules and, ultimately, to membrane brane is attached to the stable surface (pri- fusion and exocytosis ( D4, D5) to the extracellular marily fibronectin of the extracellular matrix space (ECS). in the case of fibroblasts), the cell moves for- Transcytosis is the uptake of macromolecules ward relative to the surface. This is achieved such as proteins and hormones by endocytosis with the aid of specific receptors, such as fi- on one side of the cell, and their release on the bronectin receptors in the case of fibroblasts. opposite side. This is useful for transcellular transport of the macromolecules across cell lay- ers such as endothelia. Cell Migration Most cells in the body are theoretically able to move from one place to another or migrate ( E), but only a few cell species actually do so. The sperm are probably the only cells with a special propulsion mechanism. By waving30 their whip-like tail, the sperm can travel at Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 43. D. Constitutive exozytosis 1 Activation of ARF Trans-Golgi network v-SNARE GNRP GTP GDP GDP GTP ARF-GTP (active) ARF-GDP 2 Coating (inactive) Cell Migration 3 Coatomer-coated vesicle ARF-GDP (inactive) Pi 4 Membrane 5 Exocytosis fusion Coatomer Plate 1.15 t-SNARE Plasma membrane ECS E. Cell migration 1 K+, Cl– K+, Cl– Lamellipodium Cell Support Attachment See 2 points(After A. Schwab et al.) d 15min 20 µm c 10 min Actin monomer b 5min Profilin Actin polymer a 0 min Cross-linkPhotos: K.Gabriel protein Myosin I 2 31 (Partly after H.Lodish et al.)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 44. At equilibrium potential, the chemical Electrical Membrane Potentials and gradient will drive just as many ions of species Ion Channels X in the one direction as the electrical poten- An electrical potential difference occurs due to tial does in the opposite direction. The electro- the net movement of charge during ion trans- chemical potential (Em – Ex) or so-called elec- port. A diffusion potential develops for in- trochemical driving “force”, will equal zero, stance, when ions (e.g., K+) diffuse (down a and the sum of ionic inflow and outflow or the chemical gradient; p. 20ff.) out of a cell, net flux (Ix) will also equal zero. making the cell interior negative relative to the Membrane conductance (gx), a concentra-1 Fundamentals and Cell Physiology outside. The rising diffusion potential then tion-dependent variable, is generally used to drives the ions back into the cell (potential- describe the permeability of a cell membrane driven ion transport; p. 22). Outward K+ dif- to a given ion instead of the permeability fusion persists until equilibrium is reached. At coefficient P (see Eq. 1.5 on p. 22 for conver- equilibrium, the two opposing forces become sion). Since it is relative to membrane surface equal and opposite. In other words, the sum of area, gx is expressed in siemens (S = 1/Ω) per the two or the electrochemical gradient (and m2 ( p. 22, Eq. 1.9). Ohm’s law defines the net thereby the electrochemical potential) equals ion current (Ix) per unit of membrane surface zero, and there is no further net movement of area as ions (equilibrium concentration) at a certain IX gX ! (Em – EX) [A ! m–2] [1.19] voltage (equilibrium potential). The equilibrium potential (Ex) for any spe- Ix will therefore differ from zero when the pre- cies of ion X distributed inside (i) and outside vailing membrane potential, Em, does not equal (o) a cell can be calculated using the Nernst the equilibrium potential, Ex. This occurs, for equation: example, after strong transient activation of Na+-K +-ATPase (electrogenic; p. 26): hyper- R!T [X]o EX ! ln [V] [1.17] polarization of the membrane ( A2), or when F ! zx [X]i the cell membrane conducts more than one where R is the universal gas constant (= 8.314 ion species, e.g., K+ as well as Cl– and Na+: J ! K– 1 ! mol– 1), T is the absolute temperature depolarization ( A3). If the membrane is per- (310 K in the body), F is the Faraday constant meable to different ion species, the total con- or charge per mol (= 9.65 104 A ! s ! mol– 1), z is ductance of the membrane (gm) equals the sum the valence of the ion in question (+ 1 for K+, + 2 of all parallel conductances (g1 + g2 + g3 + ...). for Ca2+, – 1 for Cl–, etc.), ln is the natural loga- The fractional conductance for the ion species rithm, and [X] is the effective concentration = X (fx) can be calculated as activity of the ion X ( p. 376). R ! T/F = 0.0267 fX gX/gm [1.20] V– 1 at body temperature (310 K). It is some- times helpful to convert ln ([X]o/[X]i) into The membrane potential, Em, can be deter- –ln ([X]i/[X]o), V into mV and ln into log be- mined if the fractional conductances and equi- fore calculating the equilibrium potential librium potentials of the conducted ions are ( p. 380). After insertion into Eq. 1.17, the known (see Eq. 1.18). Assuming K+, Na+, and Cl– Nernst equation then becomes are the ions in question, 1 [X]i Em (EK ! fK) + (ENa ! fNa) + (ECl ! fCl) [1.21] EX – 61 ! ! log [mV] [1.18] zX [X]o Realistic values in resting nerve cells are: fK = If the ion of species X is K+, and [K+]i = 140, and 0.90, fNa = 0.03, fCl = 0.07; EK = – 90 mV, ENa = [K+]o = 4.5 mmol/kg H2O, the equilibrium + 70 mV, ECl = – 83 mV. Inserting these values potential EK = – 61 ! log31 mV or – 91 mV. If the into equation 1.21 results in an Em of – 85 mV. cell membrane is permeable only to K+, the Thus, the driving forces (= electrochemical membrane potential (Em) will eventually reach potentials = Em – Ex), equal + 5 mV for K+, a value of – 91 mV, and Em will equal EK ( A1). – 145 mV for Na+, and – 2 mV for Cl–. The driv-32 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 45. A. Electrochemical potential (E m– E K) and ionic currents [K]o = [K]i = Nernst equation 4.5 mmol/L 140mmol/L 140 EK = 61· log –––– Em– EK= 0 4.5 = –91mV K+ K+ Net current IK = gK · (Em– EK) 1. Em= EK Outside Inside Electrical Potentials I 2. Hyperpolarization Em Equilibrium: I K = 0 (K+ efflux=K+ influx) + + (e.g., due to very high Na -K - ATPase activity) 3. Depolarization [K]o = 4.5 [K]i = 140 (e. g., due to Na+ influx) [K]o = 4.5 [K]i = 140 3 Na+ 2 K+ Na+ Em– EK = negative Em– EK = positive Plate 1.16 + K K+ Net K+ influx (IK negative) Net K+ efflux (IK positive) B. Single-channel recoprding (patch-clamp technique) 3 Data analysis 1 Experimental set-up 2 Current (pA) Electrode 1 Measuring unit 0Pipette solution: –50 –25 0 –25150 mmol/l NaCl Voltage (mV)+ 5mmol/l KCl Oscillograph 200 ms Clamp voltage 20mV Pipette pA Burst 2 0K+ channel Clamp voltage 0 mVCytosolic 2 side 0 Membrane patch Clamp voltage –20 mV Bath solution: 2 5 mmol/l NaCl +150 mmol/l KCl 0 2µm Clamp voltage –40 mV 2 2 Single-channel current recording 0 33(After R.Greger)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 46. ing force for K+ efflux is therefore low, though can either be left intact, or a membrane patch gK is high. Despite a high driving force for Na+, can excised for isolated study ( B1). In single- Na+ influx is low because the gNa and fNa of rest- channel recording, the membrane potential is ing cells are relatively small. Nonetheless, the kept at a preset value (voltage clamp). This per- sodium current, INa, can rise tremendously mits the measurement of ionic current in a when large numbers of Na+ channels open single channel. The measurements are plotted during an action potential ( p. 46). ( B3) as current (I) over voltage (V). The slope Electrodiffusion. The potential produced by of the I/V curve corresponds to the conduct- the transport of one ion species can also drive ance of the channel for the respective ion spe-1 Fundamentals and Cell Physiology other cations or anions through the cell mem- cies (see Eq. 1.18). The zero-current potential is brane ( p. 22), provided it is permeable to defined as the voltage at which the I/V curve them. The K+diffusion potential leads to the ef- intercepts the x-axis of the curve (I = 0). The flux of Cl–, for example, which continues until ion species producing current I can be deduced ECl = Em. According to Equation 1.18, this means from the zero-current potential. In example B, that the cytosolic Cl– concentration is reduced the zero-current potential equals – 90 mV. to 1/25 th of the extracellular concentration Under the conditions of this experiment, an (passive distribution of Cl– between cytosol and electrochemical gradient exists only for Na+ extracellular fluid). In the above example, and K+, but not for Cl– ( B). At these gradients, there was a small electrochemical Cl– potential EK = – 90 mV and ENa = + 90 mV. As EK equals the driving Cl– out of the cell (Em – ECl = – 2 mV). zero-current potential, the channel is exclu- This means that the cytosolic Cl– concentration sively permeable to K+ and does not allow is higher than in passive Cl– distribution (ECl = other ions like Na+ to pass. The channel type Em). Therefore, Cl– ions must have been ac- can also be determined by adding specific tively taken up by the cell, e.g., by a Na+- Cl– channel blockers to the system. symport carrier ( p. 29 B): active distribution Control of ion channels ( C). Channel of Cl– . open-probability is controlled by five main To achieve ion transport, membranes have a factors: variable number of channels (pores) specific ! Membrane potential, especially in Na+, Ca2+ for different ion species (Na+, Ca2+, K+, Cl–, etc.). and K+ channels in nerve and muscle fibers The conductance of the cell membrane is ( C1; pp. 46 and 50). therefore determined by the type and number ! External ligands that bind with the channel of ion channels that are momentarily open. ( C2). This includes acetylcholine on the Patch–clamp techniques permit the direct postsynaptic membrane of nicotinic synapses measurement of ionic currents through single (cation channels), glutamate (cation chan- ion channels ( B). Patch–clamp studies have nels), and glycine or GABA (Cl– channels). shown that the conductance of a membrane ! Intracellular messenger substances ( C3) does not depend on the change of the pore such as: diameter of its ion channels, but on their aver- — cAMP (e.g., in Ca2+ channels in myocardial age frequency of opening. The ion permeabil- cells and Cl– channels in epithelial cells); ity of a membrane is therefore related to the — cGMP (plays a role in muscarinergic effects open-probability of the channels in question. of acetylcholine and in excitation of the reti- Ion channels open in frequent bursts ( B2). nal rods); Several ten thousands of ions pass through the — IP3 (opening of Ca2+ channels of intracellu- channel during each individual burst, which lar Ca2+ stores); lasts for only a few milliseconds. — Small G-proteins (Ca2+ channels of the cell During a patch–clamp recording, the open- membrane); ing (0.3–3 µm in diameter) of a glass electrode — Tyrosine kinases (Cl– and K+ channels is placed over a cell membrane in such a way during apoptosis); that the opening covers only a small part of the — Ca2+ (affects K+ channels and degree of acti- membrane (patch) containing only one or a vation of rapid Na+ channels; p. 46).34 small number of ion channels. The whole cell Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 47. C. Control of ion channels 1 Membrane potential 2 K+ Acetylcholine External ligands (nicotinergic) GABA Cl– Na+ Electrical Potentials II Na+ Cl– Cl– 2+ Ca Interstice Cytosol cAMP Ca2+ Cl– Cl– IP3 cGMP Ca2+ Na+ Ca2+ Plate 1.17 pH Tyrosine kinases ATP Cl– 5 K+ Membrane stretch K+ K+ K+ Cl– 3 Intracellular 4 messenger Intracellular substances metabolites! Intracellular metabolites ( C4) such as ATP(e.g., in K+ channels in the heart and B cells inpancreatic islets) or H+ ions (e.g., in K+ chan-nels in renal epithelial cells);! Membrane stretch ( C5), the direct or in-direct (?) effects of which play a role in Ca2+channels of smooth muscle fibers and gen-erally in normal K+ and Cl– channels in swellingcells. 35 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 48. [Ca2+]i oscillation is characterized by multi- Role of Ca2+ in Cell Regulation ple brief and regular [Ca2+]i increases (Ca2+ The cytosolic Ca2+ concentration, [Ca2+]i, (ca. spikes) in response to certain stimuli or hor- 0.1 to 0.01 µmol/L) is several decimal powers mones ( B). The frequency, not amplitude, of lower than the extracellular Ca2+ concentra- [Ca2+]i oscillation is the quantitative signal for tion [Ca2+]o (ca. 1.3 mmol/L). This is because cell response. When low-frequency [Ca2+]i Ca2+ is continuously pumped from the cytosol oscillation occurs, CaM-kinase II, for example, into intracellular Ca2+ stores such as the is activated and phosphorylates only its target endoplasmic and sarcoplasmic reticulum proteins, but is quickly and completely deacti-1 Fundamentals and Cell Physiology ( p. 17 A), vesicles, mitochondria and nuclei vated ( B1, B3). High-frequency [Ca2+]i oscil- (?) or is transported out of the cell. Both lation results in an increasing degree of auto- processes occur by primary active transport phosphorylation and progressively delays the (Ca2+-ATPases) and, in the case of efflux, by ad- deactivation of the enzyme ( B3). As a result, ditional secondary active transport through the activity of the enzyme decays more and Ca2+/3 Na+ antiporters ( A1). more slowly between [Ca2+]i signals, and each To increase the cytosolic Ca2+ concentration, additional [Ca2+]i signal leads to a summation Ca2+ channels conduct Ca2+ from intracellular of enzyme activity ( B2). As with action stores and the extracellular space into the cy- potentials ( p. 46), this frequency-borne, tosol ( A2). The frequency of Ca2+ channel digital all-or-none type of signal transmission opening in the cell membrane is increased by provides a much clearer message than the ! Depolarization of the cell membrane (nerve [Ca2+]i amplitude, which is influenced by a and muscle cells); number of factors. ! Ligands (e.g., via Go proteins; p. 274); Ca2+ sensors. The extracellular Ca2+ concen- ! Intracellular messengers (e.g., IP3 and cAMP; tration [Ca2+]o plays an important role in blood p. 274ff.); coagulation and bone formation as well as in ! Stretching or heating of the cell membrane. nerve and muscle excitation. [Ca2+]o is tightly The Ca2+ channels of the endoplasmic and sar- controlled by hormones such as PTH, calcitriol coplasmic reticulum open more frequently in and calcitonin ( p. 290), and represents the response to signals such as a rise in [Ca2+]i (in- feedback signal in this control circuit flux of external Ca2+ works as the “spark” or ( p. 290). The involved Ca2+sensors are mem- trigger) or inositol tris-phosphate (IP3; A2 brane proteins that detect high [Ca2+]o levels and p. 276). on the cell surface and dispatch IP3 and DAG A rise in [Ca2+]i is a signal for many impor- (diacylglycerol) as intracellular second mes- tant cell functions ( A), including myocyte sengers with the aid of a Gq protein ( C1 and contraction, exocytosis of neurotransmitters p. 274ff.). IP3 triggers an increase in the [Ca2+]i in presynaptic nerve endings, endocrine and of parafollicular C cells of the thyroid gland. exocrine hormone secretion, the excitation of This induces the exocytosis of calcitonin, a certain sensory cells, the closure of gap junc- substance that reduces [Ca2+]o ( C2). In para- tions in various cells ( p. 19 C), the opening thyroid cells, on the other hand, a high [Ca2+]o of other types of ion channels, and the migra- reduces the secretion of PTH, a hormone that tion of leukocytes and tumor cells ( p. 30) as increases the [Ca2+]o. This activity is mediated well as thrombocyte activation and sperm mo- by DAG and PKC (protein kinase C) and, per- bilization. Some of these activities are medi- haps, by a (Gi protein-mediated; p. 274) re- ated by calmodulin. A calmodulin molecule duction in the cAMP concentration ( C3). can bind up to 4 Ca2+ ions when the [Ca2+]i rises Ca2+ sensors are also located on osteoclasts as ( A2). The Ca2+-calmodulin complexes acti- well as on renal and intestinal epithelial cells. vate a number of different enzymes, including calmodulin-dependent protein kinase II (CaM- kinase II) and myosin light chain kinase (MLCK), which is involved in smooth muscle36 contraction ( p. 70). Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 49. A. Role of Ca2+ in cell regulation [Ca2+]o Depolarization, external ligands, Ca2+ =1.3mmol/L IP3, cAMP, etc.. + 3Na 1 Ca2+ ATP Ca2+ Role of Ca2+ in Cell Regulation ? ? [Ca2+] i Ca2+ ER K+ 2 Nucleus Vesicle In striated Ca2+ muscle: [Ca2+] i Calmodulin Ca2+ =0.1–0.01 µmol/L Muscle contraction, Exocytosis (exocrine, endocrine, of transmitter), Troponin sensor excitation, gap junction closure, more frequent opening/closing of other ion channels, cell migration, etc. B. Ca2+ oscillation Plate 1.18 1 Low frequency 2 High frequency Stimulus[Ca2+]i [Ca2+]i TimeCaM- Timekinase IIactivity CaM- (After J. W. Putney, Jr.) kinase II activity Time Time Increasing auto- 3 Enzyme deactivation phosphorylation unphosphorylated Activity autophosphorylated Time C. Ca2+ sensor CalcitoninCa2+ [Ca2+]o 1 Ca2+ [Ca2+] i 2 Ca2+ Parafollicular C cell Gq PIP2 Gi Phospho- lipase C PTH te DAG IP3 yla e ATP Parathyroid en las PKC cell Ad cyc Ca2+ PKC [Ca2+] i [cAMP] [cAMP] ? 37 3Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 50. Heat is transferred in all chemical reactions. Energy Production and Metabolism The amount of heat produced upon conversion Energy is the ability of a system to perform of a given substance into product X is the same, work; both are expressed in joules (J). A poten- regardless of the reaction pathway or whether tial difference (potential gradient) is the so- the system is closed or open, as in a biological called driving “force” that mobilizes the matter system. For caloric values, see p. 228. involved in the work. Water falling from height Enthalpy change (∆H) is the heat gained or X (in meters) onto a power generator, for ex- lost by a system at constant pressure and is re- ample, represents the potential gradient in lated to work, pressure, and volume (∆H = ∆U1 Fundamentals and Cell Physiology mechanical work. In electrical and chemical + p ! ∆V). Heat is lost and ∆H is negative in ex- work, potential gradients are provided respec- othermic reactions, while heat is gained and tively by voltage (V) and a change in free en- ∆H is positive in endothermic reactions. The thalpy ∆G (J ! mol– 1). The amount of work per- second law of thermodynamics states that the formed can be determined by multiplying the total disorder (randomness) or entropy (S) of a potential difference (intensity factor) by the closed system increases in any spontaneous corresponding capacity factor. In the case of process, i.e., entropy change (∆S) 0. This the water fall, the work equals the height the must be taken into consideration when at- water falls (m) times the force of the falling tempting to determine how much of ∆H is water (in N). In the other examples, the freely available. This free energy or free en- amount work performed equals the voltage (V) thalpy (∆G) can be used, for example, to drive a times the amount of charge (C). Chemical work chemical reaction. The heat produced in the performed = ∆G times the amount of sub- process is the product of absolute temperature stance (mol). and entropy change (T · ∆S). Living organisms cannot survive without an Free enthalpy (∆G) can be calculated using adequate supply of energy. Plants utilize solar the Gibbs-Helmholtz equation: energy to convert atmospheric CO2 into oxy- ∆G ∆H – T · ∆S. [1.24] gen and various organic compounds. These, in ∆G and ∆H are approximately equal when ∆S turn, are used to fill the energy needs of approaches zero. The maximum chemical humans and animals. This illustrates how work of glucose in the body can therefore be energy can be converted from one form into determined based on heat transfer, ∆H, another. If we consider such a transformation measured during the combustion of glucose in taking place in a closed system (exchange of a calorimeter (see p. 228 for caloric values). energy, but not of matter, with the environ- Equation 1.24 also defines the conditions ment), energy can neither appear nor disap- under which chemical reactions can occur. Ex- pear spontaneously. In other words, when ergonic reactions (∆G 0) are characterized energy is converted in a closed system, the by the release of energy and can proceed spon- total energy content remains constant. This is taneously, whereas endergonic reactions (∆G described in the first law of thermodynamics, 0) require the absorption of energy and are which states that the change of internal energy not spontaneous. An endothermic reaction (= change of energy content, ∆U) of a system (∆H 0) can also be exergonic (∆G 0) when (e.g. of a chemical reaction) equals the sum of the entropy change ∆S is so large that ∆H – the work absorbed (+W) or performed (–W) by T · ∆S becomes negative. This occurs, for ex- a system and the heat lost (–Q) or gained (+Q) ample, in the endothermic dissolution of crys- by the system. This is described as: talline NaCl in water. ∆U heat gained (Q) work performed Free enthalpy, ∆G, is a concentration-de- (W) [J] and [1.22] pendent variable that can be calculated from ∆U work absorbed (W) heat lost the change in standard free enthalpy (∆G0) and (Q) [J]. [1.23] the prevailing concentrations of the sub- (By definition, the signs indicate the direction stances in question. ∆G0 is calculated assum- of flow with respect to the system under con- ing for all reaction partners that concentration38 sideration.) = 1 mol/L, pH = 7.0, T = 298 K, and p = 1013 hPa. Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 51. A. Activation energy (E a) Energy required Transitional state F for reaction to occur ( Pa) Energy Production and Metabolism Chemical potential Uncatalyzed activation energy No Ea= Pa – Pe reaction Pa´ Catalyzed activation energy (Partly after J. Koolman and K.-H. Röhm ) EductA Energy level E a´= Pa´– Pe of educt (Pe) Free enthalpy ∆G0=Pp – Pe Plate 1.19 ProductB Energy level of product (Pp) Reaction pathway B. Molecular fraction (F) when Pe > Pa C. Aerobic ATP production High-energy substrates: 55 Fats and carbohydratesEnergy (kJ·mol–1) Krebs cycle NADH 50 Ea= Pa – Pe e– O2 Respiratory chain 37° C 27° C 17° C H+ H+ H+ 45 + H gradient 0 1 2 4 6 8 10 CO2 H2O F (molecules/109 molecules) End products ATP 39 (After J.Koolman and K.-H.Röhm) (see plate 1.8B)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 52. Given the reaction called the activation energy (Ea) : Ea = Pa – Pe. It A B + C, [1.25] is usually so large ( 50 kJ ! mol– 1) that only a where A is the educt and B and C are the prod- tiny fraction (F 10– 9) of the educt molecules ucts, ∆G0 is converted to ∆G as follows: are able to provide it ( A, B). The energy [B] + [C] levels of these individual educt molecules are ∆G ∆G0 + R ! T ! ln [1.26] [A] incidentally higher than Pe, which represents or, at a temperature of 37 C, the mean value for all educt molecules. The ∆G size of fraction F is temperature-dependent [B] + [C] ∆G0 + 8.31 ! 310 ! 2.3 ! log ! [J ! mol–1] ( B). A 10 C decrease or rise in temperature1 Fundamentals and Cell Physiology [A] [1.27] lowers or raises F (and usually the reaction rate) by a factor of 2 to 4, i.e. the Q10 value of the Assuming the ∆G0 of a reaction is + 20 kJ ! mol–1 reaction is 2 to 4. (endergonic reaction), ∆G will be exergonic Considering the high Ea values of many non- ( 0) if [B] ! [C] is 104 times smaller than A: catalyzed reactions, the development of ∆G 20000+5925!log10–4 – 3.7 kJ!mol–1. enzymes as biological catalysts was a very im- [1.28] portant step in evolution. Enzymes In this case, A is converted to B and C and reac- enormously accelerate reaction rates by low- tion 1.25 proceeds to the right. ering the activation energy Ea ( A). According If [B] ! [C]/[A] = 4.2 10– 4, ∆G will equal to the Arrhenius equation, the rate constant k zero and the reaction will come to equilibrium (s– 1) of a unimolecular reaction is proportional (no net reaction). This numeric ratio is called to e–Ea/(R ! T). For example, if a given enzyme re- the equilibrium constant (Keq) of the reaction. duces the Ea of a unimolecular reaction from Keq can be converted to ∆G0 and vice versa 126 to 63 kJ ! mol– 1, the rate constant at 310 K using Equation 1.26: (37 C) will rise by e– 63000/(8.31 ! 310)/e– 126000/(8.31 ! 0 ∆G0 + R ! T ! lnKeq or 310) , i.e., by a factor of 4 ! 1010. The enzyme ∆G0 – R ! T ! lnKeq and [1.29] would therefore reduce the time required to metabolize 50% of the starting materials (t1/2) Keq e–∆G /(R ! T). [1.30] from, say, 10 years to 7 msec! The forward rate –4 Conversely, when [B] ! [C]/[A] 4.2 10 , ∆G of a reaction (mol ! L– 1 ! s– 1) is related to the will be 0, the net reaction will proceed back- product of the rate constant (s– 1) and the wards, and A will arise from B and C. starting substrate concentration (mol ! L– 1). ∆G is therefore a measure of the direction of The second law of thermodynamics also im- a reaction and of its distance from equilibrium. plies that a continuous loss of free energy oc- Considering the concentration-dependency of curs as the total disorder or entropy (S) of a ∆G and assuming the reaction took place in an closed system increases. A living organism open system (see below) where reaction prod- represents an open system which, by defini- ucts are removed continuously, e.g., in sub- tion, can absorb energy-rich nutrients and dis- sequent metabolic reactions, it follows that ∆G charge end products of metabolism. While the would be a large negative value, and that the entropy of a closed system (organism + en- reaction would persist without reaching equi- vironment) increases in the process, an open librium. system (organism) can either maintain its en- The magnitude of ∆G0, which represents tropy level or reduce it using free enthalpy. the difference between the energy levels This occurs, for example, when ion gradients (chemical potentials) of the product Pp and or hydraulic pressure differences are created educt Pe ( A), does not tell us anything about within the body. A closed system therefore has the rate of the reaction. A reaction may be very a maximum entropy, is in a true state of chemi- slow, even if ∆G0 0, because the reaction rate cal equilibrium, and can perform work only also depends on the energy level (Pa) needed once. An open system such as the body can transiently to create the necessary transitional continuously perform work while producing state. Pa is higher than Pe ( A). The additional only a minimum of entropy. A true state of40 amount of energy required to reach this level is equilibrium is achieved in only a very few Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 53. processes within the body, e.g., in the reaction stances is lower than that of ATP, but still rela-CO2 + H2O HCO3– + H+. In most cases (e.g. tively high.metabolic pathways, ion gradients), only a The free energy liberated upon hydrolysis ofsteady state is reached. Such metabolic path- ATP is used to drive hundreds of reactionsways are usually irreversible due, for example, within the body, including the active trans-to excretion of the end products. The thought membrane transport of various substances,of reversing the “reaction” germ cell adult il- protein synthesis, and muscle contraction. Ac-lustrates just how impossible this is. cording to the laws of thermodynamics, the At steady state, the rate of a reaction is more expenditure of energy in all of these reactions Energy Production and Metabolismimportant than its equilibrium. The regulation leads to increased order in living cells and,of body functions is achieved by controlling re- thus, in the organism as a whole. Life is there-action rates. Some reactions are so slow that it fore characterized by the continuous reduc-is impossible to achieve a sufficient reaction tion of entropy associated with a correspond-rate with enzymes or by reducing the concen- ing increase in entropy in the immediate en-tration of the reaction products. These are vironment and, ultimately, in the universe.therefore endergonic reactions that requirethe input of outside energy. This can involve“activation” of the educt by attachment of ahigh-energy phosphate group to raise the Pe. ATP (adenosine triphosphate) is the univer-sal carrier and transformer of free enthalpywithin the body. ATP is a nucleotide thatderives its chemical energy from energy-richnutrients ( C). Most ATP is produced by oxi-dation of energy-rich biological moleculessuch as glucose. In this case, oxidation meansthe removal of electrons from an electron-rich(reduced) donor which, in this case, is a carbo-hydrate. CO2 and H2O are the end products ofthe reaction. In the body, oxidation (or electrontransfer) occurs in several stages, and a portionof the liberated energy can be simultaneouslyused for ATP synthesis. This is therefore acoupled reaction ( C and p. 17 B). The stan-dard free enthalpy ∆G0 of ATP hydrolysis, ATP ADP + Pi [1.31]is – 30.5 kJ ! mol– 1. According to Eq. 1.27, the∆G of reaction 1.31 should increase when theratio ([ADP] ! [Pi)]/[ATP] falls below the equi-librium constant Keq of ATP hydrolysis. The factthat a high cellular ATP concentration doesindeed yield a ∆G of approximately – 46 to– 54 kJ ! mol– 1 shows that this also applies inpractice. Some substances have a much higher ∆G0 ofhydrolysis than ATP, e.g., creatine phosphate(– 43 kJ ! mol– 1). These compounds react withADP and Pi to form ATP. On the other hand, theenergy of ATP can be used to synthesize othercompounds such as UTP, GTP and glucose-6-phosphate. The energy content of these sub- 41 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 54. 2 Nerve and Muscle, Physical Work rate of ca. 25 cm/day. Slow axon transport (ca. Neuron Structure and Function 1 mm/day) plays a role in the regeneration of An excitable cell reacts to stimuli by altering its severed neurites. membrane characteristics ( p. 32). There are Along the axon, the plasma membrane of two types of excitable cells: nerve cells, which the soma continues as the axolemma ( A1,2). transmit and modify impulses within the The axolemma is surrounded by oligodendro- nervous system, and muscle cells, which con- cytes ( p. 338) in the central nervous system tract either in response to nerve stimuli or au- (CNS), and by Schwann cells in the peripheral tonomously ( p. 59). nervous system ( A1,2). A nerve fiber con- The human nervous system consists of sists of an axon plus its sheath. In some neu- more than 1010 nerve cells or neurons. The neu- rons, Schwann cells form multiple concentric ron is the structural and functional unit of the double phospholipid layers around an axon, nervous system. A typical neuron (motor neu- comprising the myelin sheath ( A1,2) that in- ron, A1) consists of the soma or cell body sulates the axon from ion currents. The sheath and two types of processes: the axon and den- is interrupted every 1.5 mm or so at the nodes drites. Apart from the usual intracellular or- of Ranvier ( A1). The conduction velocity of ganelles ( p. 8 ff.), such as a nucleus and mi- myelinated nerve fibers is much higher than tochondria ( A2), the neuron contains neuro- that of unmyelinated nerve fibers and in- fibrils and neurotubules. The neuron receives creases with the diameter of the nerve fiber afferent signals (excitatory and inhibitory) ( p. 49 C). from a few to sometimes several thousands of A synapse ( A3) is the site where the axon other neurons via its dendrites (usually ar- of a neuron communicates with effectors or borescent) and sums the signals along the cell other neurons (see also p. 50 ff.). With very few membrane of the soma (summation). The axon exceptions, synaptic transmissions in mam- arises from the axon hillock of the soma and is mals are mediated by chemicals, not by electri- responsible for the transmission of efferent cal signals. In response to an electrical signal in neural signals to nearby or distant effectors the axon, vesicles ( p. 1.6) on the presynaptic (muscle and glandular cells) and adjacent neu- membrane release transmitter substances rons. Axons often have branches (collaterals) (neurotransmitters) by exocytosis ( p. 30). that further divide and terminate in swellings The transmitter diffuses across the synaptic called synaptic knobs or terminal buttons. If the cleft (10–40 nm) to the postsynaptic mem- summed value of potentials at the axon hillock brane, where it binds to receptors effecting exceeds a certain threshold, an action poten- new electrical changes ( A3). Depending on tial ( p. 46) is generated and sent down the the type of neurotransmitter and postsynaptic axon, where it reaches the next synapse via the receptor involved, the transmitter will either terminal buttons ( A1,3) described below. have an excitatory effect (e.g., acetylcholine in Vesicles containing materials such as pro- skeletal muscle) or inhibitory effect (e.g., gly- teins, lipids, sugars, and transmitter sub- cine in the CNS) on the postsynaptic mem- stances are conveyed from the Golgi complex brane. Since the postsynaptic membrane nor- of the soma ( p. 13 F) to the terminal buttons mally does not release neurotransmitters and the tips of the dendrites by rapid axonal (with only few exceptions), nerve impulses transport (40 cm/day). This type of antero- can pass the synapse in one direction only. The grade transport along the neurotubules is pro- synapse therefore acts like a valve that ensures moted by kinesin, a myosin-like protein, and the orderly transmission of signals. Synapses the energy required for it is supplied by ATP are also the sites at which neuronal signal ( p. 16). Endogenous and exogenous sub- transmissions can be modified by other (exci- stances such as nerve growth factor (NGF), tatory or inhibitory) neurons. herpes virus, poliomyelitis virus, and tetanus toxin are conveyed by retrograde transport42 from the peripheral regions to the soma at a Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 55. A. Nerve cell structure and function 2 Myelinated and unmyelinated nerve fibers1 Neuron and Unmyelinated fibers synapse Neuron Structure and Function Dendrites Soma Axon hillock Mito- chondria Axon (neurite) Schwann cells Axolemma Plate 2.1 Endoneurium Myelinated fibers Myelin Nodes sheath of Ranvier Electron microscopic view, 1:22000 magnification. Photograph courtesy of Dr. Lauren A. Langford Nucleus of a Schwann cell Collaterals Presynaptic ending (terminal button) Electrical 3 Synapse (diagram) transmission Presynaptic membrane Chemical transmission (neurotransmitter) Synaptic cleft Electrical Postsynaptic transmission membrane 43Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 56. tive) diffusion potential drives K+ back into the Resting Membrane Potential cell and rises until large enough to almost An electrical potential difference, or mem- completely compensate for the K+ concentra- brane potential (Em), can be recorded across tion gradient driving the K+-ions out of the cell the plasma membrane of living cells. The ( A4). As a result, the membrane potential, potential of unstimulated muscle and nerve Em, is approximately equal to the K+ equi- cells, or resting potential, amounts to – 50 to librium potential EK ( p. 32). – 100 mV (cell interior is negative). A resting ! Cl– distribution: Since the cell membrane is potential is caused by a slightly unbalanced2 Nerve and Muscle, Physical Work also conductive to Cl– (gCl greater in muscle distribution of ions between the intracellular cells than in nerve cells), the membrane poten- fluid (ICF) and extracellular fluid (ECF) ( B). tial (electrical driving “force”) expels Cl– ions The following factors are involved in establish- from the cell ( A4) until the Cl– concentration ing the membrane potential (see also p. 32 ff.). gradient (chemical driving “force”) drives ! Maintenance of an unequal distribution of them back into the cell at the same rate. The in- ions: The Na+-K+-ATPase ( p. 26) continu- tracellular Cl– concentration, [Cl–]i, then con- ously “pumps” Na+ out of the cell and K+ into it tinues to rise until the Cl– equilibrium poten- ( A2). As a result, the intracellular K+ concen- tial equals Em ( A5). [Cl–]i can be calculated tration is around 35 times higher and the intra- using the Nernst equation ( p. 32, Eq. 1.18). cellular Na+ concentration is roughly 20 times Such a “passive” distribution of Cl– between lower than the extracellular concentration the intra- and extracellular spaces exists only ( B). As in any active transport, this process as long as there is no active Cl– uptake into the requires energy, which is supplied by ATP. Lack cell ( p. 34). of energy or inhibition of the Na+-K+-ATPase results in flattening of the ion gradient and ! Why is Em less negative than EK? Although breakdown of the membrane potential. the conductances of Na+ and Ca2+ are very low in resting cells, a few Na+ and Ca2+ ions con- Because anionic proteins and phosphates present in stantly enter the cell ( A4, 5 ). This occurs be- high concentrations in the cytosol are virtually un- able to leave the cell, purely passive mechanisms cause the equilibrium potential for both types (Gibbs–Donnan distribution) could, to a slight extent, of ions extends far into the positive range, re- contribute to the unequal distribution of diffusable sulting in a high outside-to-inside electrical ions ( A1). For reasons of electroneutrality, and chemical driving “force” for these ions [K++Na+]ICF [K++Na+]ECF and [Cl–]ICF [Cl–]ECF. ( B; p. 32f.). This cation influx depolarizes However, this has practically no effect on the the cell, thereby driving K+ ions out of the cell development of resting potentials. (1 K+ for each positive charge that enters). If ! Low resting Na+ and Ca2+ conductance, gNa, Na+-K+-ATPase did not restore these gradients gCa: The membrane of a resting cell is only very continuously (Ca2+ indirectly via the 3 Na+/Ca2+ slightly permeable to Na+ and Ca2+, and the exchanger; p. 36), the intracellular Na+ and resting gNa comprises only a small percentage Ca2+ concentrations would increase continu- of the total conductance ( p. 32 ff.). Hence, ously, whereas [K+]i would decrease, and EK the Na+ concentration difference ( A3–A5) and Em would become less negative. cannot be eliminated by immediate passive All living cells have a (resting) membrane diffusion of Na+ back into the cell. potential, but only excitable cells such as nerve and muscle cells are able to greatly change the ! High K+conductance, gK: It is relatively easy ion conductance of their membrane in re- for K+ ions to diffuse across the cell membrane sponse to a stimulus, as in an action potential (gK 90% of total conductance; p. 32ff.). Be- ( p. 46). cause of the steep concentration gradient ( point 1), K+ ions diffuse from the ICF to the ECF ( A3). Because of their positive charge, the diffusion of even small amounts of K+ ions44 leads to an electrical potential (diffusion poten- tial) across the membrane. This (inside nega- Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 57. A. Causes and effects of resting membrane potentials 1 Passive ion distribution 2 Active Na+-K+-pump 3 K+ diffusion potential ECF ICF ECF ICF ECF 0 ICF mV Resting Membrane Potential Membrane Proteins– Passive Proteins– Proteins– Phosphates– Phosphates– Phosphates– K+ K+ CI– – CI K+ K+ ATP Na+ K+ K+ Na+ + Na Na+ K+ chemical gradient rises Na+ Na+ Active transport via ATPase K+ diffuses from ICF to ECF Potential develops Plate 2.2 4 Potential drives CI– from ICF to ECF 5 End state: Resting membrane potential 0 0 ECF ICF ECF ICF mV mV Proteins– Proteins– Phosphates– Phosphates– – – CI CI CI – CI – Passive K+ K+ + K K+ Na+ Na+ + Na+ Na B. Typical “effective” concentrations and equilibrium potentials of important ions in skeletal muscle (at 37°C) “Effective” concentration (mmol/kg H2O) Equilibrium Interstice (ECF) Cell (ICF) potential K+ 4.5 160 – 95 mV Na+ 144 7 + 80 mV Ca2+ 1.3 0.0001– 0.00001 +125 to +310 mV (After Conway) H+ 4·10–5 (pH 7.4) 10–4 (pH 7.0) – 24 mV CI– 114 7 – 80 mV 45 HCO3– 28 10 – 27 mVDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 58. resulting in a hyperpolarizing afterpotential Action Potential ( A1). Increased Na+-K+-ATPase pumping An action potential is a signal passed on rates (electrogenic; p. 28) can contribute to through an axon or along a muscle fiber that this afterpotential. influences other neurons or induces muscle Very long trains of action potentials can be contraction. Excitation of a neuron occurs if the generated (up to 1000/s in some nerves) since membrane potential, Em, on the axon hillock of the quantity of ions penetrating the mem- a motor neuron, for example ( p. 42), or on brane is very small (only ca. 1/100 000 th the the motor end-plate of a muscle fiber changes number of intracellular ions). Moreover, the2 Nerve and Muscle, Physical Work from its resting value ( p. 44) to a less nega- Na+-K+-ATPase ( p. 26) ensures the continu- tive value (slow depolarization, A1). This ous restoration of original ion concentrations depolarization may be caused by neu- ( p. 46). rotransmitter-induced opening of postsynap- During an action potential, the cell remains tic cation channels ( p. 50) or by the (elec- unresponsive to further stimuli; this is called trotonic) transmission of stimuli from the sur- the refractory period. In the absolute refractory roundings ( p. 48). If the Em of a stimulated period, no other action potential can be trig- cell comes close to a critical voltage or thresh- gered, even by extremely strong stimuli, since old potential ( A1), “rapid” voltage-gated Na+ Na+ channels in depolarized membranes can- channels are activated ( B4 and B1 ! B2). not be activated ( B3). This is followed by a This results in increased Na+ conductance, gNa relative refractory period during which only ac- ( p. 32), and the entry of Na+ into the cell tion potentials of smaller amplitudes and rates ( A2). If the threshold potential is not of rise can be generated, even by strong reached, this process remains a local (sub- stimuli. The refractory period ends once the threshold) response. membrane potential returns to its resting Once the threshold potential is reached, the value ( e.g. p. 59 A). cell responds with a fast all-or-none depolari- The extent to which Na+ channels can be ac- zation called an action potential, AP ( A1). tivated and, thus, the strength of the Na+ cur- The AP follows a pattern typical of the specific rent, INa, depends on the pre-excitatory resting cell type, irregardless of the magnitude of the potential, not the duration of depolarization. stimulus that generated it. Large numbers of The activation of the Na+ channels reaches a Na+ channels are activated, and the influxing maximum at resting potentials of ca. – 100 mV Na+ accelerates depolarization which, in turn, and is around 40% lower at – 60 mV. In mam- increases gNa and so on (positive feedback). As mals, Na+ channels can no longer be activated a result, the Em rapidly collapses (0.1 ms in at potentials of – 50 mV and less negative nerve cells: fast depolarization phase or up- values ( B3). This is the reason for the abso- sweep) and temporarily reaches positive levels lute and relative refractory periods (see above) (overshooting, + 20 to + 30 mV). The gNa drops and the non-excitability of cells after the ad- before overshooting occurs ( A2) because ministration of continuously depolarizing sub- the Na+ channels are inactivated within 0.1 ms stances such as suxamethonium ( p. 56). An ( B2 ! B3). The potential therefore reverses, increased extracellular Ca2+ concentration and restoration of the resting potential, the re- makes it more difficult to stimulate the cell be- polarization phase of the action potential, cause the threshold potential becomes less begins. Depolarization increases (relatively negative. On the other hand, excitability in- slowly) the open-probability of voltage-gated creases (lower threshold) in hypocalcemic K+ channels. This increases the potassium con- states, as in muscle spasms in tetany ductance, gK, thereby accelerating repolariza- ( p. 290). tion. The special features of action potentials in In many cases, potassium conductance, gK is cardiac and smooth muscle fibers are de- still increased after the original resting poten- scribed on pages 192, 70 and 59 A. tial has been restored ( A2), and Em tem-46 porarily approaches EK ( pp. 44 and 32 ff.), Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 59. A. Action potential (1) and ion conductivity (2) (nerve and skeletal muscle) 1 2 + “Overshoot” + (20 – 30 mV) 0 0 – Action – Repolariza Membrane potential E m (mV) potential Ion conductance g tion gNa ion Action Depolarizat E m (mV) potential Action Potential gK After-hyper- Threshold polarization (ca. –70 to –90mV)Resting potential Resting Pre- GK depolari- sation Resting GNa 0 Plate 2.3 Time Time ca. 1ms ca. 1ms B. Voltage-gated Na+ channel 1. Closed, [mV] activatable + Depolarization 0 – –90 mV [mV] Resting potential Na+ + 0 2. Open – Na+ channel Depolarization (first 0.5 ms) Tetrodotoxin Complete repolarization Veratridine Batrachotoxin 4 Tetrodotoxin Na+ (TTX) [mV] Out 3. Closed, + inactivated 0 – Reversal of potential and start of repolarization In 47Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 60. Action potentials normally run forward (or- Propagation of Action Potentials in thodromic) because each segment of nerve Nerve Fiber fiber becomes refractory when an action Electrical current flows through a cable when potential passes ( A1b and p. 46). If, however, voltage is applied to it. The metal wire inside the impulses are conducted backwards (anti- the cable is well insulated and has very low- dromic) due, for example, to electrical stimula- level resistance, reducing current loss to a tion of nerve fibers from an external source minimum. As a result, it can conduct electric- ( p. 50), they will terminate at the next syn- ity over long distances. Nerve fibers, especially apse (valve-like function, p. 42).2 Nerve and Muscle, Physical Work unmyelinated ones ( p. 42), have a much Although the continuous generation of ac- greater internal longitudinal resistance (Ri) tion potentials in the immediately adjacent and are not well insulated from their sur- fiber segment guarantees a refreshed signal, roundings. Therefore, the cable-like, elec- this process is rather time-consuming ( B1). trotonic transmission of neural impulses The conduction velocity, θ, in unmyelinated dwindles very rapidly, so the conducted im- (type C) nerve fibers ( C) is only around pulses must be continuously “refreshed” by 1 m/s. Myelinated (types A and B) nerve fibers generating new action potentials ( p. 46). ( C) conduct much faster (up to 80 m/s = 180 Propagation of action potentials: The start mph in humans). In the internode regions, a of an action potential is accompanied by a brief myelin sheath ( p. 42) insulates the nerve influx of Na+ into the nerve fiber ( A1a). The fibers from the surroundings; thus, longitudi- cell membrane that previously was inside nal currents strong enough to generate action negative now becomes positive ( + 20 to potentials can travel further down the axon + 30 mV), thus creating a longitudinal poten- (ca. 1.5 mm) ( A2). This results in more rapid tial difference with respect to the adjacent, conduction because the action potentials are still unstimulated nerve segments (internal generated only at the unmyelinated nodes of –70 to –90 mV; p. 44). This is followed by a Ranvier, where there is a high density of Na+ passive electrotonic withdrawal of charge from channels. This results in rapid, jump-like pas- the adjacent segment of the nerve fiber, caus- sage of the action potential from node to node ing its depolarization. If it exceeds threshold, (saltatory propagation). The saltatory length is another action potential is created in the adja- limited since the longitudinal current (1 to cent segment and the action potential in the 2 nA) grows weaker with increasing distance previous segment dissipates ( A1b). ( B2). Before it drops below the threshold Because the membrane acts as a capacitor, level, the signal must therefore be refreshed by the withdrawal of charge represents a capaci- a new action potential, with a time loss of tating (depolarizing) flow of charge that be- 0.1 ms. comes smaller and rises less steeply as the spa- Since the internal resistance, Ri, of the nerve tial distance increases. Because of the rela- fiber limits the spread of depolarization, as de- tively high Ri of nerve fiber, the outward loops scribed above, the axon diameter (2r) also af- of current cross the membrane relatively close fects the conduction velocity, θ ( C). Ri is pro- to the site of excitation, and the longitudinal portional to the cross-sectional area of the current decreases as it proceeds towards the nerve fiber (πr2), i.e., Ri 1/r2. Thick fibers periphery. At the same time, depolarization in- therefore require fewer new APs per unit of creases the driving force (= Em – EK; p. 32) for length, which is beneficial for θ. Increases in K+ outflow. K+ fluxing out of the cell therefore fiber diameter are accompanied by an increase accelerates repolarization. Hence, distal action in both fiber circumference (2πr) and mem- potentials are restricted to distances from brane capacity, K (K r). Although θ decreases, which the capacitative current suffices to the beneficial effect of the smaller Ri predomi- depolarize the membrane quickly and strongly nates because of the quadratic relationship. enough. Otherwise, the Na+ channels will be deactivated before the threshold potential is48 reached ( p. 46). Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 61. Propagation of Action Potentials in Nerve Fiber A. Continuous (1a, 1b) and saltatory propagation (2) of action potentials AP AP Myelin sheath + + Na Na Action potential (AP) + charge balance Depolarization Na + Na Continuous Action potential Rest (balancing current) 1a charge balance Internode Saltatory Refractory + + Na Na AP Depo- Node Depolarization larization Plate 2.4 1b 2 B. Pulse propagation (action currents) in myelinated and unmyelinated nerve fibers AP AP2 mm 2 mm 1 nA 1 nA AP 1 2 ms 2 0.1 ms 0.1 ms C. Classification of nerve fibers (in humans) Fiber type Function according to fiber type Diameter Conduction (Lloyd and Hunt types I–IV) (µm) rate (m/s) Aα Skeletal muscle efferent, afferents in muscle 11 – 16 60 – 80 spindles (Ib) and tendon organs (Ib) Aβ Mechanoafferents of skin (II) 6 –11 30 – 60 Aγ Muscle spindle efferents Aδ Skin afferents (temperature 1– 6 2 – 30 and „fast“ pain) (III) B Sympathetic preganglionic; 3 3 – 15 visceral afferents C Skin afferents (“slow” pain); 0.5–1.5 sympathetic postganglionic afferents (IV) (unmyelinated) 0.25 – 1.5 49 (After Erlanger and Gasser)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 62. provide not only simple 1 : 1 connections, but Artificial Stimulation of Nerve Cells also serve as switching elements for the When an electrical stimulus is applied to a nervous system. They can facilitate or inhibit nerve cell from an external source, current the neuronal transmission of information or flows from the positive stimulating electrode process them with other neuronal input. At the (anode) into the neuron, and exits at the nega- chemical synapse, the arrival of an action tive electrode (cathode). The nerve fiber below potential (AP) in the axon ( A1,2 and p. 48) the cathode is depolarized and an action triggers the release of the transmitter from the potential is generated there if the threshold presynaptic axon terminals. The transmitter2 Nerve and Muscle, Physical Work potential is reached. then diffuses across the narrow synaptic cleft The conduction velocity of a nerve can be (ca. 30 nm) to bind postsynaptically to recep- measured by placing two electrodes on the tors in the subsynaptic membrane of a neuron skin along the course of the nerve at a known or of a glandular or muscle cell. Depending on distance from each other, then stimulating the the type of transmitter and receptor involved, nerve (containing multiple neurons) and rec- the effect on the postsynaptic membrane may ording the time it takes the summated action either be excitatory or inhibitory, as is de- potential to travel the known distance. The scribed below. conduction velocity in humans is normally 40 Transmitters are released by regulated exo- to 70 m ! s– 1. Values below 40 m ! s– 1 are con- cytosis of so-called synaptic vesicles ( A1). sidered to be pathological. Each vesicle contains a certain quantum of Accidental electrification. Exposure of the neurotransmitters. In the case of the motor body to high-voltage electricity, especially end-plate ( p. 56), around 7000 molecules of low-frequency alternating current (e.g., in an acetylcholine (ACh) are released. Some of the electrical outlet) and low contact resistance vesicles are already docked on the membrane (bare feet, bathtub accidents), primarily affects (active zone), ready to exocytose their con- the conduction of impulses in the heart and tents. An incoming action potential functions can cause ventricular fibrillation ( p. 200). as the signal for transmitter release ( A1,2). Direct current usually acts as a stimulus The higher the action potential frequency in only when switched on or off: High-frequency the axon the more vesicles release their con- alternating current ( 15 kHz), on the other tents. An action potential increases the open hand, cannot cause depolarization but heats probability of voltage-gated Ca2+ channels in the body tissues. Diathermy works on this the presynaptic membrane (sometimes oscil- principle. lating), thereby leading to an increase in the cytosolic Ca2+ concentration, [Ca2+]i ( A1, 3 and p. 36). Extracellular Mg2+ inhibits this Synaptic Transmission process. Ca2+ binds to synaptotagmin ( A1), Synapses connect nerve cells to other nerve which triggers the interaction of syntaxin and cells (also applies for certain muscle cells) as SNAP-25 on the presynaptic membrane with well as to sensory and effector cells (muscle synaptobrevin on the vesicle membrane, and glandular cells). thereby triggering exocytosis of already Electrical synapses are direct, ion-conduct- docked vesicles (approximately 100 per AP) ing cell–cell junctions through channels (con- ( A1, 4). On the other hand, Ca2+ activates cal- nexons) in the region of gap junctions cium-calmodulin-dependent protein kinase-II ( p. 16 f.). They are responsible for the con- (CaM-kinase-II; A5, and p. 36), which acti- duction of impulses between neighboring vates the enzyme synapsin at the presynaptic smooth or cardiac muscle fibers (and some- terminal. As a result, vesicles dock anew on the times between neurons in the retina and in the active zone. CNS) and ensure also communication between Synaptic facilitation (= potentiation). If an neighboring epithelial or glial cells. action potential should arrive at the presynap- Chemical synapses utilize (neuro)transmit- tic terminal immediately after another AP (AP50 ters for the transmission of information and frequency approx. 30 Hz), the cytosolic Ca2+ Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 63. A. Chemical synapse Na+ AP 1 0 2 Presynaptic action potential mV –80 Synaptic Transmission I Calmodulin PresynapticCa2+ ending 3 Ca2+ Ca2+ influx 0 ICa nA Vesicle –0.5 CaM- kinase II Synapto- tagminActive zone Plate 2.5 Transmitter 4 Transmitter 1 in cleft Ionotropic Transmitter mmol/L Synaptic receptor cleft or release Metabotropic 0 receptor Cation channel Postsynaptic cell (Partly after Llinás) 5 Synapsin CaM- kinase II Vesicle preparationActive zone Docking mV Transmitter binding 0 K+ to receptors or Na+ (Ca2+) EPSP1 EPSP2 EPSP3 Signal chain K+ 6 7 Ca2+ (Na+) Summation Postsynaptic –90 51 action potential (see plate B.)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 64. concentration will not yet drop to the resting threshold. This type of temporal summation value, and residual Ca2+ will accumulate. As a therefore increases the excitability of the post- result, the more recent rise in [Ca2+]i builds on synaptic neuron ( C). the former one. [Ca2+]i rises to a higher level Inhibitory transmitters include substances after the second stimulus than after the first, as glycine, GABA (γ-aminobutyric acid), and and also releases more transmitters. Hence, acetylcholine (at M2 and M3 receptors; the first stimulus facilitates the response to the p. 82). They increase the conductance, g, of second stimulus. Muscle strength increases at the subsynaptic membrane only to K+ (e.g., the high stimulus frequencies for similar reasons metabotropic GABAB receptor.) or Cl– (e.g., the2 Nerve and Muscle, Physical Work ( p. 67 A). ionotropic glycine and GABAA receptors; F). Among the many substances that act as ex- The membrane usually becomes hyper- citatory transmitters are acetylcholine (ACh) polarized in the process (ca. 4 mV max.). In- and glutamate (Glu). They are often released creases in gK occur when Em approaches EK together with co-transmitters which modulate ( p. 44). However, the main effect of this in- the transmission of a stimulus (e.g., ACh to- hibitory postsynaptic potential IPSP ( D) is not gether with substance P, VIP or galanin; Glu hyperpolarization–which works counter to with substance P or enkephalin). If the trans- EPSP-related depolarization (the IPSP is some- mitter’s receptor is an ion channel itself times even slightly depolarizing). Instead, the (ionotropic receptor or ligand-gated ion chan- IPSP-related increase in membrane conduct- nel; A6 and F), e.g., at the N-cholinergic syn- ance short circuits the electrotonic currents of apse ( p. 82), the channels open more often the EPSP (high gK or gCl levels). Since both EK and allow a larger number of cations to enter and ECl are close to the resting potential (Na+, sometimes Ca2+) and leave the cell (K+). ( p. 44), stabilization occurs, that is, the EPSP Other, so-called metabotropic receptors in- is cancelled out by the high K+ and Cl– short- fluence the channel via G proteins that control circuit currents. As a result, EPSP-related channels themselves or by means of “second depolarization is reduced and stimulation of messengers” ( A7 and F). Because of the high postsynaptic neurons is inhibited ( D). electrochemical Na+ gradient ( p. 32), the Termination of synaptic transmission ( E) number of incoming Na+ ions is much larger can occur due to inactivation of the cation than the number of exiting K+ ions. Ca2+ can channels due to a conformational change in also enter the cell, e.g., at the glutamate-NMDA the channel similar to the one that occurs receptor ( F). The net influx of cations leads during an action potential ( p. 46). This very to depolarization: excitatory postsynaptic rapid process called desensitization also func- potential (EPSP) (maximum of ca. 20 mV; B). tions in the presence of a transmitter. Other The EPSP begins approx. 0.5 ms after the ar- terminating pathways include the rapid enzy- rival of an action potential at the presynaptic matic decay of the transmitter (e.g., acetylcho- terminal. This synaptic delay (latency) is line) while still in the synaptic cleft, the re-up- caused by the relatively slow release and diffu- take of the transmitter (e.g., noradrenaline) sion of the transmitter. into the presynaptic terminal or uptake into A single EPSP normally is not able to extraneuronal cells (e.g., in glial cells of the generate a postsynaptic (axonal) action poten- CNS), endocytotic internalization of the recep- tial (APA), but requires the triggering of a large tor ( p. 28), and binding of the transmitter to number of local depolarizations in the den- a receptor on the presynaptic membrane (au- drites. Their depolarizations are transmitted toceptor). In the latter case, a rise in gK and a electrotonically across the soma ( p. 48) and drop in gCa can occur, thus inhibiting transmit- summed on the axon hillock (spatial summa- ter release, e.g., of GABA via GABAB receptors or tion; B). Should the individual stimuli arrive of noradrenaline via α2-adrenoceptors ( F at different times (within approx. 50 ms of and p. 86). each other), the prior depolarization will not have dissipated before the next one arrives,52 and summation will make it easier to reach Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 65. B. Spatial summation of stimuli AP1 mV –70 EPSP1 AP2 –90 ms Dendrite –70 EPSP2 Synaptic Transmission II AP3 –90 Neuron (soma) –70 EPSP3 mV 0 –90 Action potential –10 (APA) Axon hillock APA –30 Electrotonic currents (depolarizing) Plate 2.6 –50 Summed EPSP Axon –70 –90 0 2 4 6 8 ms C. Temporal summation of stimuli AP1 Dendrite mV –70 EPSP1 –90 Neuron (soma) AP2 mV –70 EPSP2 0 Action potential –10 (APA) –90 –30 Summed EPSP Elapsed APA time –50 Electrotonic currents (depolarizing) –70 –90 0 2 4 6 8 ms 53Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 66. D. Effect of IPSP on postsynaptic stimulation APE Excitatory transmitter mV –70 EPSP2 Nerve and Muscle, Physical Work –90 ms API K+ Inhibitory Na+ transmitter –70 Depolarization IPSP Electrotonic transmission –90 “Short-circuit” via – K+- (and/or Cl -) channels mV Summation K+ –70 EPSP+IPSP Hyperpolarization –90 ms Postsynaptic neuron Electrotonic currents hyperpolarize axon hillock To axon hillock E. Termination of transmitter action Extraneuronal uptake Reuptake Glial cell, etc. Inhibition Presynaptic of exocytose ending Diffusion out of cleft gK gCa Autoceptor Postsynaptic cell Enzymatic breakdown of transmitter Rapid inactivation of cation channel (desensitization) Internalization54 of receptor Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 67. F. Neurotransmitters in the central nervous system Transmitter Receptor Receptor Effect subtypes types Ion conductance Second messenger Na+ K+ Ca2+ Cl– cAMP IP3/ DAG Synaptic Transmission III u. IV Acetylcholine Nicotinic Muscarinic: M1, M2, M3 ADH V1 (= vasopressin) V2 CCK (= cholecystokinin) CCKA–B Dopamine D1, D5 D2 GABA GABAA,GABA C (= γ-aminobutyric acid) GABAB Plate 2.7 u. 2.8 Glutamate (aspartate) AMPA Kainat NMDA m-GLU Glycine _ Histamine H1 H2 Neurotensin _ α1 (A–D) Norepinephrine, epinephrine α2 (A–C) β1 –3 Neuropeptide Y (NPY) Y 1–2 Opioid peptides µ, δ, κ Oxytocin _ Purines P1 : A1 A2a P2X P2Y Serotonin 5-HT1 (5-hydroxytryptamine) 5-HT2 5-HT3 5-HT4–7 Somatostatin (= SIH) SRIF Tachykinin NK1–3 Amino acids Inhibits or promotes Catecholamines Peptides Ionotropic receptor Metabotropic receptor DAG (ligand-gated (G protein-mediated cAMP Others ion channel) effect) ATP PIP2 IP3 55 (Modified from F. E. Bloom)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 68. “force” (= Em – ENa,K; p. 32 ff.) becomes Motor End-plate smaller when Em is less negative. The transmission of stimuli from a motor axon ENa,K is the common equilibrium potential for Na+ and to a skeletal muscle fiber occurs at the motor K+ and amounts to approx. 0 mV. It is also called the end-plate, MEP ( A), a type of chemical syn- reversal potential because the direction of IEP (= INa apse ( p. 50 ff.). The transmitter involved is + IK), which enters the cell when Em is negative (Na+ acetylcholine (ACh, cf. p. 82), which binds to influx K+ outflow), reverses when Em is positive (K+ the N(nicotinergic)-cholinoceptors of the sub- outflow Na+ influx). As a result, synaptic muscle membrane ( A3). N-cholino- IEP n ! po ! γ ! (Em – ENa, K) [A] [2.1]2 Nerve and Muscle, Physical Work ceptors are ionotropic, that is, they also func- Because neurally induced EPPs in skeletal tion as ion channels ( A4). The N-cholinocep- muscle are much larger (depolarization by ca. tor of the MEP (type NM) has 5 subunits (2α, 1β, 70 mV) than neuronal EPSPs (only a few mV; 1γ, 1δ), each of which contains 4 membrane- p. 50 ff.), single motor axon action potentials spanning α-helices ( p. 14). are above threshold. The EPP is transmitted The channel opens briefly ( B1) (for ap- electrotonically to the adjacent sarcolemma, prox. 1 ms) when an ACh molecule binds to the where muscle action potentials are generated two α-subunits of an N-cholinoceptor ( A4). by means of voltage-gated Na+ channels, re- Unlike voltage-gated Na+-channels, the open- sulting in muscle contraction. probability po of the NM-cholinoceptor is not Termination of synaptic transmission in increased by depolarization, but is determined MEPs occurs (1) by rapid degradation of ACh in by the ACh concentration in the synaptic cleft the synaptic cleft by acetylcholinesterase local- ( p. 50 ff.). ized at the subsynaptic basal membrane, and The channel is specific to cations such as Na+, (2) by diffusion of ACh out of the synaptic cleft K+, and Ca2+. Opening of the channel at a rest- ( p. 82). ing potential of ca. 90 mV leads mainly to an A motor end-plate can be blocked by certain influx of Na+ ions (and a much lower outflow of poisons and drugs, resulting in muscular K +; pp. 32 ff. and 44). Depolarization of the weakness and, in some cases, paralysis. subsynaptic membrane therefore occurs: end- Botulinum neurotoxin, for example, inhibits the plate potential (EPP). Single-channel currents discharge of neurotransmitters from the ves- of 2.7 pA ( B1) are summated to yield a min- icles, and α-bungarotoxin in cobra venom iature end-plate current of a few nA when blocks the opening of ion channels. Curare-like spontaneous exocytosis occurs and a vesicle substances such as (+)-tubocurarine are used releases a quantum of ACh activating thou- as muscle relaxants in surgical operations. sands of NM-cholinoceptors ( B2). Still, this is They displace ACh from its binding site (com- not enough for generation of a postsynaptic ac- petitive inhibition) but do not have a depolariz- tion potential unless an action potential trans- ing effect of their own. Their inhibitory effect mitted by the motor neuron triggers exocyto- can be reversed by cholinesterase inhibitors sis of around a hundred vesicles. This opens such as neostigmine (decurarinization). These around 200,000 channels at the same time, agents increase the concentration of ACh in the yielding a neurally induced end-plate current synaptic cleft, thereby displacing curare. Entry (IEP) of ca. 400 nA ( B3). End-plate current, IEP, of anticholinesterase agents into intact syn- is therefore dependent on: apses leads to an increase in the ACh concen- ! the number of open channels, which is tration and, thus, to paralysis due to permanent equal to the total number of channels (n) times depolarization. ACh-like substances such as the open-probability (po), where po is deter- suxamethonium have a similar depolarizing mined by the concentration of ACh in the syn- effect, but decay more slowly than ACh. In this aptic cleft (up to 1 mmol/L); case, paralysis occurs because permanent ! the single-channel conductance γ (ca. depolarization also permanently inactivates 30 pS); Na+ channels near the motor end-plate on the ! and, to a slight extent, the membrane sarcolemma ( p. 46).56 potential, Em, since the electrical driving Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 69. A. Motor end-plate Myelin sheath Motor axon 1 Motor end-plate Schwann cell Motor End-plate Mitochondrion Nerve Vesicle ending Finger2 Postsynaptic Basement folds membrane Plate 2.9 Muscle fiber 3 Acetylcholine vesicle Presynaptic membrane Synaptic cleft with basement membrane Nerve ending Postsynaptic membrane (sarcolemma) 4 K+ ACh Active Cholinergic γ zone N-receptors α α Muscle fiber (Ca2+) Na+ (Partly after Akert and Peper) B. End-plate currents 1 Quantum 100-200 Quanta 2.7pA 400 nA 4 nA 0 1 2 3 0 1 2 3 0 1 2 3 Time (ms) Time (ms) Time (ms) 1 Single-channel current 2 Miniature end-plate 3 Nerve-induced 57 current end-plate current (After Neher and Sakmann (1) and after Peper et al. (2))Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 70. Slow-twitch fibers are the least fatigable and Motility and Muscle Types are therefore equipped for sustained perform- Active motility (ability to move) is due to ance. They have high densities of capillaries either the interaction of energy-consuming and mitochondria and high concentrations of motor proteins (fueled by ATPase) such as my- fat droplets (high-energy substrate reserves) osin, kinesin and dynein with other proteins and the red pigment myoglobin (short-term O2 such as actin or the polymerization and storage). They are also rich in oxidative depolymerization of actin and tubulin. Cell di- enzymes ( p. 72). Fast-twitch fibers are vision (cytokinesis), cell migration ( p. 30), mainly responsible for brief and rapid contrac-2 Nerve and Muscle, Physical Work intracellular vesicular transport and cytosis tions. They are quickly fatigued (FF FR) and ( p. 12f.), sperm motility ( p. 306f.), axonal are rich in glycogen (FF FR) but contain little transport ( p. 42), electromotility of hair cells myoglobin (FF FR). ( p. 366), and ciliary motility ( p. 110) are The fiber type distribution of a muscle de- examples of cell and organelle motility. pends on the muscle type. Motor units of the S The muscles consist of cells (fibers) that type predominate in “red” muscles such as the contract when stimulated. Skeletal muscle is soleus muscle, which helps to maintain the responsible for locomotion, positional change, body in an upright position, whereas the F type and the convection of respiratory gases. Car- predominates in “white” muscles such as the diac muscle ( p. 190 ff.) is responsible for gastrocnemius muscle, which is involved in pumping the blood, and smooth muscle running activity. Each fiber type can also be ( p. 70) serves as the motor of internal organs converted to the other type. If, for example, the and blood vessels. The different muscle types prolonged activation of fast-twitch fibers leads are distinguished by several functional charac- to a chronic increase in the cytosolic Ca2+ con- teristics ( A). centration, fast-twitch fibers will be converted to slow-twitch fibers and vice versa. Graded muscle activity is possible because a Motor Unit of Skeletal Muscle variable number of motor units can be re- Unlike some types of smooth muscle (single- cruited as needed. The more motor units a unit type; p. 70) and cardiac muscle fibers, muscle has, the more finely graded its contrac- which pass electric stimuli to each other tions. Contractions are much finer in the exter- through gap junctions or nexus ( A; p. 16f.), nal eye muscles, for example, which have skeletal muscle fibers are not stimulated by around 2000 motor units, than in the lumbri- adjacent muscle fibers, but by motor neurons. cal muscles, which have only around 100 In fact, muscle paralysis occurs if the nerve is motor units. The larger the number of motor severed. units recruited, the stronger the contraction. One motor neuron together with all muscle The number and type of motor units recruited fibers innervated by it is called a motor unit depends on the type of movement involved (MU). Muscle fibers belonging to a single (fine or coarse movement, intermittent or per- motor unit can be distributed over large por- sistent contraction, reflex activity, voluntary or tions (1 cm2) of the muscle cross-sectional involuntary movement, etc.). In addition, the area. To supply its muscle fibers, a motor neu- strength of each motor unit can be increased ron splits into collaterals with terminal by increasing the frequency of neuronal im- branches ( p. 42). A given motor neuron may pulses, as in the tetanization of skeletal muscle supply only 25 muscle fibers (mimetic muscle) ( p. 67 A). or well over 1000 (temporal muscle). Two types of skeletal muscle fibers can be distinguished: S – slow-twitch fibers (type 1) and F – fast-twitch fibers (type 2), including two subtypes, FR (2 A) and FF (2 B). Since each motor unit contains only one type of fiber, this58 classification also applies to the motor unit. Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 71. A. Structure and function of heart, skeletal and smooth muscle Smooth muscle Cardiac muscle (striated) Skeletal muscle (striated) Structure and function Motor end-plates None None Yes Fibers < Fusiform, short (– 0.2 mm) Branched < Cylindrical, long (– 15 cm) Mitochondria Few Many Few (depending on muscle type) Nucleus per fiber 1 1 Multiple Sarcomeres None < Yes, length – 2.6 µm < Yes, length – 3.65 µm Electr. coupling Some (single-unit type) Yes (functional syncytium) No Sarcoplasmic Little developed Moderately developed Highly developed reticulum 2+ Troponin Ca “switch” Calmodulin/caldesmon Troponin Some spontaneous rhythmic activity –1 Pacemaker (1s–1 – 1h–1) Yes (sinus nodes ca.1s ) No (requires nerve stimulus) Response to stimulus Change in tone or rhythm frequency All or none Graded Tetanizable Yes No Yes Work range Length-force curve In rising At peak ofDespopoulos, Color Atlas of Physiology © 2003 Thieme is variable length-force curve (see 2.15E) length-force curve (see 2.15E) + 20 Absolutely Relatively Absolutely “Spike” refractory refractory + 50 refractory + 20 Response mV 0 mV 0 to stimulus mV 0All rights reserved. Usage subject to terms and conditions of license. Spontaneous – 20 – 20 fluctuation – 50 – 40 – 60 Potential –100 – 60 – 100 Muscle 0 200 400 600 0 100 200 300 400 0 10 20 30 tension ms ms ms Plate 2.10 Muscle types, motor unit 59
  • 72. changes in the head–neck segment allow the Contractile Apparatus of Striated myosin head to “tilt” when interacting with Muscle actin (sliding filaments; p. 62). The muscle cell is a fiber ( A2) approximately Actin is a globular protein molecule (G- 10 to 100 µm in diameter. Skeletal muscles actin). Four hundered such molecules join to fibers can be as long as 15 cm. Meat “fibers” form F-actin, a beaded polymer chain. Two of visible with the naked eye are actually bundles the twisted protein filaments combine to form of muscle fibers that are around 100 to an actin filament ( B), which is positioned by 1000 µm in diameter ( A1). Each striated the equally long protein nebulin.2 Nerve and Muscle, Physical Work muscle fiber is invested by a cell membrane Tropomyosin molecules joined end-to-end called the sarcolemma, which surrounds the (40 nm each) lie adjacent to the actin filament, sarcoplasm (cytoplasm), several cell nuclei, and a troponin (TN) molecule is attached every mitochondria (sarcosomes), substances in- 40 nm or so ( B). Each troponin molecule volved in supplying O2 and energy ( p. 72), consists of three subunits: TN-C, which has and several hundreds of myofibrils. two regulatory bindings sites for Ca2+ at the So-called Z lines or, from a three-dimen- amino end, TN-I, which prevents the filaments sional aspect, Z plates (plate-like proteins; from sliding when at rest ( p. 62), and TN-T, B) subdivide each myofibril ( A3) into ap- which interacts with TN-C, TN-I, and actin. prox. 2 µm long, striated compartments called The sarcomere also has another system of sarcomeres ( B). When observed by (two-di- filaments ( B) formed by the filamentous mensional) microscopy, one can identify alter- protein titin (connectin). Titin is more than nating light and dark bands and lines (hence 1000 nm in length and has some 30 000 amino the name “striated muscle”) created by the acids (Mr 3000 kDa). It is the longest known thick myosin II filaments and thin actin fila- polypeptide chain and comprises 10% of the ments ( B; for myosin I, see p. 30). Roughly total muscle mass. Titin is anchored at its carb- 2000 actin filaments are bound medially to the oxyl end to the M plate and, at the amino end, Z plate. Thus, half of the filament projects into to the Z plate ( p. 66 for functional descrip- two adjacent sarcomeres ( B). The region of tion). the sarcomere proximal to the Z plate contains The sarcolemma forms a T system with only actin filaments, which form a so-called several transverse tubules (tube-like invagina- I band ( B). The region where the actin and tions) that run perpendicular to the myofibrils myosin filaments overlap is called the A band. ( p. 63 A). The endoplasmic reticulum The H zone solely contains myosin filaments ( p. 10 ff.) of muscle fibers has a characteris- (ca. 1000 per sarcomere), which thicken tic shape and is called the sarcoplasmic reti- towards the middle of the sarcomere to form culum (SR; p. 63 A). It forms closed cham- the M line (M plate). The (actin) filaments are bers without connections between the intra- anchored to the sarcolemma by the protein and extracellular spaces. Most of the chambers dystrophin. run lengthwise to the myofibrils, and are Each myosin filament consists of a bundle of therefore called longitudinal tubules ca. 300 myosin-II molecules ( B). Each ( p. 63 A). The sarcoplasmic reticulum is molecule has two globular heads connected by more prominently developed in skeletal flexible necks (head and neck = subfragment muscle than in the myocardium and serves as a S1; formed after proteolysis) to the filamen- Ca2+ storage space. Each T system separates tous tail of the molecule (two intertwined α- the adjacent longitudinal tubules, forming tri- helices = subfragment S2) ( C). Each of the ads ( p. 63 A, B). heads has a motor domain with a nucleotide binding pocket (for ATP or ADP + Pi) and an actin binding site. Two light protein chains are located on each neck of this heavy molecule (220 kDa): one is regulatory (20 kDa), the60 other essential (17 kDa). Conformational Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 73. A. Ultrastructure of striated muscle fibers Contractile Apparatus of Striated Muscle Sarkomere 100–1000 µm 10 – 100 µm 1µm 1 Bundle of fibers 2 Muscle fiber (myocyte) 3 Myofibril B. Sarcomere structure 6 nm ∼1.2 µm Actin Plate 2.11 Tropomyosin Troponin Sarcomere H zone Actin filament Actin Z disk filament Titin Myosin filament Z disk M disk A band 1.6 µm Myosin filament Myosin head Myosin molecule 10 nm I band 6 nm M disk C. Myosin II molecule Motor domain Actin- binding P domain Nucleotide-2 pocketnm P (ATP or ADP) Regulatory light chain Essential light chain Neck Shaft (150nm) (flexible) Head 61 20nm (After D.M.Warshaw)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 74. ATP ( p. 72) is essential for filament sliding Contraction of Striated Muscle and, hence, for muscle contraction. Due to Stimulation of muscle fibers. The release of their ATPase activity, the myosin heads acetylcholine at the motor end-plate of skeletal ( p. 60) act as the motors (motor proteins) of muscle leads to an end-plate current that this process. The myosin-II and actin filaments spreads electrotonically and activates voltage- of a sarcomere ( p. 60) are arranged in such a gated Na+ channels in the sarcolemma way that they can slide past each other. The ( p. 56). This leads to the firing of action myosin heads connect with the actin filaments potentials (AP) that travel at a rate of 2 m/s at a particular angle, forming so-called cross-2 Nerve and Muscle, Physical Work along the sarcolemma of the entire muscle bridges ( C1). Due to a conformational change fiber, and penetrate rapidly into the depths of in the region of the nucleotide binding site of the fiber along the T system ( A). myosin-II ( p. 61 C), the spatial extent of The conversion of this excitation into a con- which is increased by concerted movement of traction is called electromechanical coupling the neck region, the myosin head tilts down, ( B). In the skeletal muscle, this process drawing the thin filament a length of roughly begins with the action potential exciting volt- 4 nm ( C2). The second myosin head may also age-sensitive dihydropyridine receptors move an adjacent actin filament. The head (DHPR) of the sarcolemma in the region of the then detaches and “tenses” in preparation for triads. The DHPR are arranged in rows, and the next “oarstroke” when it binds to actin directly opposite them in the adjacent mem- anew ( C3). brane of the sarcoplasmic reticulum (SR) are Kinesin, another motor protein ( pp. 42 u. rows of Ca2+ channels called ryanodine recep- 58), independently advances on the micro- tors (type 1 in skeletal muscle: RYR1). Every tubule by incremental movement of its two other RYR1 is associated with a DHPR ( B2). heads (8 nm increments), as in tug-of-war. In RYR1 open when they directly “sense” by me- this case, fifty percent of the cycle time is chanical means an AP-related conformational “work time” (duty ratio = 0.5). Between two change in the DHPR. In the myocardium, on the consecutive interactions with actin in skeletal other hand, each DHPR is part of a voltage- muscle, on the other hand, myosin-II “jumps” gated Ca2+ channel of the sarcolemma that 36 nm (or multiples of 36, e.g. 396 nm or more opens in response to an action potential. Small in rapid contractions) to reach the next (or the quantities of extracellular Ca2+ enter the cell 11th) suitably located actin binding site ( C3, through this channel, leading to the opening of jump from a to b). Meanwhile, the other my- myocardial RYR2 (so-called trigger effect of osin heads working on this particular actin Ca2+ or Ca2+ spark; B3). Ca2+ ions stored in filament must make at least another 10 to 100 the SR now flow through the opened RYR1 or oarstrokes of around 4 nm each. The duty ratio RYR2 into the cytosol, increasing the cytosolic of a myosin-II head is therefore 0.1 to 0.01. This Ca2+ concentration [Ca2+]i from a resting value division of labor by the myosin heads ensures of ca. 0.01 µmol/L to over 1 µmol/L ( B1). In that a certain percentage of the heads will al- skeletal muscle, DHPR stimulation at a single ways be ready to generate rapid contractions. site is enough to trigger the coordinated open- When filament sliding occurs, the Z plates ing of an entire group of RYR1, thereby increas- approach each other and the overlap region of ing the reliability of impulse transmission. The thick and thin filaments becomes larger, but increased cytosolic Ca2+ concentration satu- the length of the filaments remains un- rates the Ca2+ binding sites on troponin-C, changed. This results in shortening of the thereby canceling the troponin-mediated in- I band and H zone ( p. 60). When the ends of hibitory effect of tropomyosin on filament the thick filaments ultimately bump against sliding ( D). It is still unclear whether this the Z plate, maximum muscle shortening oc- type of disinhibition involves actin–myosin curs, and the ends of the thin filaments overlap binding or the detachment of ADP and Pi, as ( p. 67 C). Shortening of the sarcomere there- described below. fore occurs at both ends of the myosin bundle,62 but in opposite directions. Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 75. A. The sarcotubular system of myocytes (muscle fibers) T system Sarcoplasmic AP (transverse tubules) reticulum (longitudinal tubules) AP Contraction of Striated Muscle I Sarcolemma (cell membrane) Triads Mitochondrion (After Porter and Franzini-Armstrong) B. Ca2+ as mediator between electrical stimulus and contraction Plate 2.12 T system – 90 mV DHPR RYR1 Sarco- Rest AP plasmatic Ca2+ reticulum Low [Ca2+]i Stimulus [Ca2+]i 2 Skeletal Cytosol AP muscle Contraction DHPR 0 10 20 30 ms with Ca2+ channel RYR2 AP +30 mV Ca2+ High [Ca2+]i 3 Myocardium 1 Ca2+ release C. Sliding filaments Actin-myosin II binding Strong Weak Strong Myosin II ATP Pi Pi ADP ATP a a a b Actin 4 nm 36 nm or multiple 1 Strong binding 2 Work phase 3 Resting phase (ca. 90% of time; other 63 (ca.10% of time) myosin heads are meanwhile active)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 76. Contraction cycle ( C and D). Each of the Parvalbumin, a protein that occurs in the cy- two myosin heads (M) of a myosin-II molecule tosol of fast-twitch muscle fibers ( type F; bind one ATP molecule in their nucleotide p. 58), accelerates muscle relaxation after binding pocket. The resulting M-ATP complex short contractions by binding cytosolic Ca2+ in lies at an approx. 90 angle to the rest of the exchange for Mg2+. Parvalbumin’s binding af- myosin filament ( D4). In this state, myosin finity for Ca2+ is higher than that of troponin, has only a weak affinity for actin binding. Due but lower than that of SR’s Ca2+-ATPase. It to the influence of the increased cytosolic Ca2+ therefore functions as a “slow” Ca2+ buffer. concentration on the troponin – tropomyosin The course of the filament sliding cycle as2 Nerve and Muscle, Physical Work complex, actin (A) activates myosin’s ATPase, described above mainly applies to isotonic resulting in hydrolysis of ATP (ATP ADP + Pi) contractions, that is, to contractions where and the formation of an A-M-ADP-Pi com- muscle shortening occurs. During strictly plex ( D1). Detachment of Pi (inorganic isometric contractions where muscular ten- phosphate) from the complex results in a con- sion increases but the muscle length remains formational change of myosin that increases unchanged, the sliding process tenses elastic the actin–myosin association constant by four components of a muscle, e.g. titin ( p. 66), powers of ten (binding affinity now strong). and then soon comes to a halt. Afterwards, the The myosin heads consequently tilt to a 40 A-M-ATP complex ( D3) probably transforms angle ( D2a), causing the actin and myosin directly into A-M-ADP-Pi ( D1). filaments to slide past each other. The release The muscle fibers of a dead body do not pro- of ADP from myosin ultimately brings the my- duce any ATP. This means that, after death, Ca2+ osin heads to their final position, a 45 angle is no longer pumped back into the SR, and the ( D2b). The remaining A-M complex (rigor ATP reserves needed to break down stable A-M complex) is stable and can again be trans- complexes are soon depleted. This results in formed into a weak bond when the myosin stiffening of the dead body or rigor mortis, heads bind ATP anew (“softening effect” of ATP). which passes only after the actin and myosin The high flexibility of the muscle at rest is im- molecules in the muscle fibers decompose. portant for processes such as cardiac filling or the relaxing of the extensor muscles during rapid bending movement. If a new ATP is bound to myosin, the subsequent weakening of the actin–myosin bond allows the realign- ment of the myosin head from 45 to 90 ( D3, 4), the position preferred by the M-ATP complex. If the cytosolic Ca2+ concentration re- mains 10– 6 mol/L, the D1 to D4 cycle will begin anew. This depends mainly on whether subsequent action potentials arrive. Only a portion of the myosin heads that pull actin fila- ments are “on duty” (low duty ratio; see p. 62) to ensure the smoothness of contractions. The Ca2+ ions released from the sarco- plasmic reticulum (SR) are continuously pumped back to the SR due to active transport by Ca2+-ATPase ( pp. 17 A and 26), also called SERCA ( p. 16). Thus, if the RYR-mediated re- lease of Ca2+ from the SR is interrupted, the cy- tosolic Ca2+ concentration rapidly drops below 10– 6 mol/L and filament sliding ceases (resting position; D, upper left corner).64 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 77. D. Work cycle of sliding filaments (isotonic contraction) DHPR with (heart) and with- Action out (muscle) Ca2+channel potential RYR T system Contraction of Striated Muscle II Myosin Longitudinal ATP Ca2+ tubule Tropomyosin Actin TroponinResting position ATP- Pi [Ca2+]i ase [Ca2+]i ADP 1µmol/l = 1–10 µmol/l Plate 2.13 45° 90° Ca2+ ATP 1 Actin-myosin binding, ATP cleavage 50° 90° 4 Loosening of actin–myosin bond (“softening” effect of ATP), myosin heads erect Pi 2a Myosin heads tilt ATP due to Pi release 45° 50° 3 ATP binding With ATP AD P Without ATP Stable “rigor complex” 65 persists 2b Final head position (rigor mortis) after ADP releaseDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 78. with the magnitude of depolarization. The Mechanical Features of Skeletal magnitude of contraction of tonus fibers is Muscle regulated by variation of the cytosolic Ca2+ con- Action potentials generated in muscle fibers centration (not by action potentials!) increase the cytosolic Ca2+ concentration In contrast, the general muscle tone (reflex [Ca2+]i, thereby triggering a contraction tone), or the tension of skeletal muscle at rest, (skeletal muscle; p. 36 B; myocardium; is attributable to the arrival of normal action p. 194). In skeletal muscles, gradation of potentials at the individual motor units. The contraction force is achieved by variable re- individual contractions cannot be detected be-2 Nerve and Muscle, Physical Work cruitment of motor units ( p. 58) and by cause the motor units are alternately (asyn- changing the action potential frequency. A chronously) stimulated. When apparently at single stimulus always leads to maximum Ca2+ rest, muscles such as the postural muscles are release and, thus, to a maximum single twitch in this involuntary state of tension. Resting of skeletal muscle fiber if above threshold (all- muscle tone is regulated by reflexes or-none response). Nonetheless, a single ( p. 318 ff.) and increases as the state of atten- stimulus does not induce maximum shorten- tiveness increases. ing of muscle fiber because it is too brief to Types of contractions ( B). There are keep the sliding filaments in motion long different types of muscle contractions. In enough for the end position to be reached. isometric contractions, muscle force (“ten- Muscle shortening continues only if a second sion”) varies while the length of the muscle re- stimulus arrives before the muscle has mains constant. (In cardiac muscle, this also completely relaxed after the first stimulus. represents isovolumetric contraction, because This type of stimulus repetition leads to in- the muscle length determines the atrial or cremental mechanical summation or super- ventricular volume.) In isotonic contractions, position of the individual contractions ( A). the length of the muscle changes while muscle Should the frequency of stimulation become force remains constant. (In cardiac muscle, this so high that the muscle can no longer relax at also represents isobaric contraction, because all between stimuli, sustained maximum con- the muscle force determines the atrial or traction of the motor units or tetanus will ventricular pressure.) In auxotonic contrac- occur ( A). This occurs, for example, at 20 Hz tions, muscle length and force both vary simul- in slow-twitch muscles and at 60–100 Hz in taneously. An isotonic or auxotonic contrac- fast-twitch muscles ( p. 58). The muscle tion that builds on an isometric one is called an force during tetanus can be as much as four afterloaded contraction. times larger than that of single twitches. The Muscle extensibility. A resting muscle con- Ca2+ concentration, which decreases to some taining ATP can be stretched like a rubber extent between superpositioned stimuli, re- band. The force required to start the stretching mains high in tetanus. action ( D, E; extension force at rest) is very Rigor ( p. 2.13) as well as contracture, small, but increases exponentially when the another state characterized by persistent muscle is under high elastic strain (see resting muscle shortening, must be distinguished tension curve, D). A muscle’s resistance to from tetanus. Contracture is not caused by ac- stretch, which keeps the sliding filaments in tion potentials, but by persistent local depolari- the sarcomeres from separating, is influenced zation due, for example, to increased extra- to a small extent by the fascia (fibrous tissue). cellular K+ concentrations (K+ contracture) or The main factor, however, is the giant filamen- drug-induced intracellular Ca2+ release, e.g., in tous elastic molecule called titin (or connectin; response to caffeine. The contraction of so- 1000 nm long, Mr = 3 to 3.7 MDa) which is in- called tonus fibers (specific fibers in the exter- corporated in the sarcomere (6 titin molecules nal eye muscles and in muscle spindles; per myosin filament). In the A band region of p. 318) is also a form of contracture. Tonus the sarcomere ( p. 61 B), titin lies adjacent to fibers do not respond to stimuli according to a myosin filament and helps to keep it in the66 the all-or-none law, but contract in proportion center of the sarcomere. Titin molecules in the Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 79. A. Muscle strength at increasing and decreasing stimulus frequencies Mechanical Features of Skeletal Muscle I Stimulus Range of summation muscle force Single contractions Tetanus Isometric 0 2 4 6 8 10 Time (s) B. Types of contractions Isometric Isotonic Force Resting tension curve 0 0 Length Isotonic, then After- Plate 2.14 Auxotonic isometric loaded Isometric Isotonic Rest Rest contraction contraction C. Isometric muscle force relative to sarcomere length 100 80 Isometric muscle force Skeletal muscle (% of maximum) 60 Range of max. force Cardiac 40 muscle 20 0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 Lmax 2.05 2.20 1.90 Actin Myosin Sarcomere Sarcomere length (µm) 3.65 1.50 (skeletal muscle) 67 (After Gordon et al.)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 80. I band region are flexible and function as “elas- force of cardiac muscle at rest is greater than tic bands” that counteract passive stretching of that of skeletal muscle ( E1, 2). a muscle and influence its shortening velocity. Skeletal muscle normally functions in the plateau region of its length–force curve, The extensibility of titin molecules, which can whereas cardiac muscle tends to operate in the stretch to up to around ten times their normal length in skeletal muscle and somewhat less in cardiac ascending limb (below Lmax) of its length–force muscle, is mainly due to frequent repetition of the curve without a plateau ( C, E1, 2). Hence, PEVK motif (proline-glutamate-valine-lysine). In very the ventricle responds to increased diastolic strong muscle extension, which represents the filling loads by increasing its force develop-2 Nerve and Muscle, Physical Work steepest part of the resting extensibility curve ( D), ment (Frank–Starling mechanism; p. 204). globular chain elements called immunoglobulin C2 In cardiac muscle, extension also affects domains also unfold. The quicker the muscle troponin’s sensitivity to Ca2+, resulting in a stretches, the more sudden and crude this type of “shock absorber” action will be. steeper curve ( E2). Action potentials in cardiac muscle are of The length (L) and force (F) or “tension” of a much longer duration than those in skeletal muscle are closely related ( C, E). The total muscle ( p. 59 A) because gK temporarily force of a muscle is the sum of its active force decreases and gCa increases for 200 to 500 ms and its extension force at rest, as was ex- after rapid inactivation of Na+ channels. This plained above. Since the active force is deter- allows the slow influx of Ca2+, causing the ac- mined by the magnitude of all potential actin- tion potential to reach a plateau. As a result, the myosin interactions, it varies in accordance refractory period does not end until a contrac- with the initial sarcomere length ( C, D). tion has almost subsided ( p. 59 A). There- Skeletal muscle can develop maximum active fore, tetanus cannot be evoked in cardiac (isometric) force (F0) from its resting length muscle. (Lmax; sarcomere length ca. 2 to 2.2 µm; C). Unlike skeletal muscle, cardiac muscle has When the sarcomeres shorten (L Lmax), part no motor units. Instead, the stimulus spreads of the thin filaments overlap, allowing only across all myocardial fibers of the atria and forces smaller than F0 to develop ( C). When subsequently of the ventricles generating an L is 70% of Lmax (sarcomere length: 1.65 µm), all-or-none contraction of both atria and, the thick filaments make contact with the Z thereafter, both ventricles. disks, and F becomes even smaller. In addition, In cardiac muscle but not in skeletal muscle, a greatly pre-extended muscle (L Lmax) can the duration of an action potential can change develop only restricted force, because the the force of contraction, which is controlled by number of potentially available actin–myosin the variable influx of Ca2+ into the cell. bridges is reduced ( C). When extended to The greater the force (load), the lower the 130% or more of the Lmax, the extension force at velocity of an (isotonic) contraction (see velo- rest becomes a major part of the total muscle city–force diagram, F1). Maximal force and a force ( E). small amount of heat will develop if shorten- The length–force curve corresponds to the ing does not occur. The maximal velocity (bi- cardiac pressure–volume diagram in which ceps: ca. 7 m/s) and a lot of heat will develop in ventricular filling volume corresponds to muscle without a stress load. Light loads can muscle length, and ventricular pressure corre- therefore be picked up more quickly than sponds to muscle force; p. 202. Changes in heavy loads ( F2). The total amount of energy the cytosolic Ca2+ concentration can modify consumed for work and heat is greater in the pressure–volume relationship by causing a isotonic contractions than in isometric ones. change in contractility ( p. 203 B2). Muscle power is the product of force and the Other important functional differences be- shortening velocity: N · m · s– 1 = W ( F1, tween cardiac muscle and skeletal muscle are colored areas). listed below (see also p. 59 A): Since skeletal muscle is more extensible68 than the cardiac muscle, the passive extension Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 81. D. Active and passive components of muscle force (skeletal muscle) Mechanical Features of Skeletal Muscle II 100 (% of maximum force) Active muscle Muscle force force Passive resting tension force Relative muscle length 0 (length at max. 80 90 100 force = 100%) 1.6 1.8 2.2 Sarcomere length (µm) E. Length-force curve for skeletal and cardiac muscle Plate 2.15 1 Striated muscle 2 Cardiac muscle Total force working range working range Total force 200 200 % of maximum active force% of maximum active force Normal Active Resting Normal force tension force 100 100 Active Resting force tension force 0 0 65 100 135 80 100 120 Relative muscle length Relative muscle length (length at max. force, L max=100%) (length at max. force, L max= 100 %) F. Muscle force (or load) and shortening velocity Maximum velocity (Vmax) 1 100 2 light Shortening velocity Fast Power with Load (% of Vmax) small load Shortening Slow large load heavy Time 0 Load = muscle force 69Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 82. pendent and, in many cases, spontaneous (my- Smooth Muscle ogenic tonus). The second type, multi-unit Smooth muscle (SmM) consists of multiple SmM, contracts primarily due to stimuli from layers of spindle-shaped cells. It is involved in the autonomic nervous system (neurogenic the function of many organs (stomach, in- tonus). This occurs in structures such as the testine, gall bladder, urinary bladder, uterus, arterioles, spermatic ducts, iris, ciliary body, bronchi, eyes, etc.) and the blood vessels, and the muscles at the roots of the hair. Since where it plays an important role in circulatory these SmM cells generally are not connected control. SmM contains a special type of F- by gap junctions, stimulation remains local-2 Nerve and Muscle, Physical Work actin-tropomyosin and myosin II filaments ized, as in the motor units of the skeletal ( p. 60), but lacks troponin and myofibrils. muscle. Furthermore, it has no distinct tubular system Smooth muscle tonus is regulated by the and no sarcomeres (nonstriated). It is there- degree of depolarization (e.g., through stretch fore called smooth muscle because of this lack or pacemaker cells) as well as by transmitter of striation (see p. 59 A for further differences substances (e.g., acetylcholine or noradrena- in the muscle types). SmM filaments form a line) and numerous hormones (e.g., estrogens, loose contractile apparatus arranged approxi- progesterone and oxytocin in the uterus and mately longitudinally within the cell and at- histamine, angiotensin II, adiuretin, serotonin tached to discoid plaques (see B for model), and bradykinin in vascular muscle). An in- which also provide a mechanical means for crease in tonus will occur if any of these factors cell–cell binding of SmM. Smooth muscle can directly or indirectly increases the cytosolic shorten much more than striated muscle. Ca2+ concentration to more than 10– 6 mol/L. The membrane potential of the SmM cells of The Ca2+ influx comes mainly from extracellu- many organs (e.g., the intestine) is not con- lar sources, but a small portion comes from in- stant, but fluctuates rhythmically at a low tracellular stores ( B1). Ca2+ ions bind to cal- frequency (3 to 15 min– 1) and amplitude (10 to modulin (CM) ( B2), and Ca2+-CM promotes 20 mV), producing slow waves. These waves contraction in the following manner. trigger a burst of action potentials (spikes) Regulation at myosin II ( B3): The Ca2+-CM when they exceed a certain threshold poten- complex activates myosin light chain kinase tial. The longer the slow wave remains above (MLCK), which phosphorylates myosin’s regu- the threshold potential, the greater the num- latory light chain (RLC) in a certain position, ber and frequency of the action potentials it thereby enabling the myosin head to interact produces. A relatively sluggish contraction oc- with actin ( B6). curs around 150 ms after a spike ( p. 59 A, left Regulation at the actin level ( B4). The panel). Tetanus occurs at relatively low spike Ca2+-CM complex also binds with caldesmon frequencies ( p. 66). Hence, SmM is con- (CDM), which then detaches from the actin– stantly in a state of a more or less strong con- tropomyosin complex, thus making it available traction (tonus or tone). The action potential of for filament sliding ( B6). Phosphorylation of SmM cells of some organs has a plateau similar CDM by protein kinase C (PK-C) also seems to to that of the cardiac action potential be able to induce filament sliding ( B5). ( p. 59 A, middle panel). Factors that lead to a reduction of tonus are: There are two types of smooth muscles reduction of the cytosolic Ca2+ concentration ( A). The cells of single-unit SmM are electri- to less than 10– 6 mol/L ( B7 ), phosphatase cally coupled with each other by gap junctions activity ( B8), and PK-C if it phosphorylates ( pp. 18 and 50). Stimuli are passed along another position on the RLC ( B9). from cell to cell in organs such as the stomach, When length–force curves are recorded for intestine, gallbladder, urinary bladder, ureter, smooth muscle, the curve shows that muscle uterus, and some types of blood vessels. force decreases continuously while muscle Stimuli are generated autonomously from length remains constant. This property of a within the SmM, partly by pacemaker cells). In muscle is called plasticity.70 other words, the stimulus is innervation-inde- Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 83. A. Smooth muscle fibers according to type of stimulation 1 Single-unit fibers Electrical coupling 2 Multi-unit fibers (gap junctions) Stimulated by autonomic nerve Spontaneous stimulation Local contraction General contraction Stomach, intestine, uterus, blood vessels, etc. Arterioles, deferent duct, iris, etc. Smooth Muscle B. Regulation of smooth muscle contraction Depolarization, transmitter, hormones, stretch Intermediate filaments Adhesive plaques Nucleus Myocyte 1 Plate 2.16 Actin-myosin filaments Ca2+ Ca2+ Ca2+ 7 Thickening zones RLC Myosin II [Ca2+]i Ca2+ [Ca2+]i Smooth ER < 10–6 mol/l (Ca2+ stores) > 10–6 mol/l Caldesmon (CDM) 2 Ca2+ CM Calmodulin binding Actin-tropomyosin Low muscle tone 9 ATP Ca2+ CM 4 2+ CDM Ca CM P MLCK 3 8 PK-C P ATP P Release of actin or Phosphatase ADP 5 PK-C ATP Phosphorylation of myosin II CDM P 6 P 71 Contraction: Increased tone Filaments slideDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 84. constant ( p. 75 B). The several minutes that Energy Supply for Muscle Contraction pass before this steady state is achieved are Adenosine triphosphate (ATP) is a direct bridged by anaerobic energy production, in- source of chemical energy for muscle contrac- creased O2 extraction from the blood and tion ( A, pp. 40 and 64). However, a muscle depletion of short-term O2 reserves in the cell contains only a limited amount of ATP– muscle (myoglobin). The interim between the only enough to take a sprinter some 10 to 20 m two phases is often perceived as the “low or so. Hence, spent ATP is continuously re- point” of physical performance. generated to keep the intracellular ATP con- The O2 affinity of myoglobin is higher than2 Nerve and Muscle, Physical Work centration constant, even when large quanti- that of hemoglobin, but lower than that of res- ties of it are needed. The three routes of ATP re- piratory chain enzymes. Thus, myoglobin is generation are ( B ): normally saturated with O2 and can pass on its 1. Dephosphorylation of creatine phosphate oxygen to the mitochondria during brief arte- 2. Anaerobic glycolysis rial oxygen supply deficits. 3. Aerobic oxidation of glucose and fatty acids. The endurance limit, which is some 370 W Routes 2 and 3 are relatively slow, so creatine ( 0.5 HP) in top athletes, is mainly dependent phosphate (CrP) must provide the chemical on the speed at which O2 is supplied and on energy needed for rapid ATP regeneration. ADP how fast aerobic oxidation takes place. When derived from metabolized ATP is immediately the endurance limit is exceeded, steady state transformed to ATP and creatine (Cr) by mito- cannot occur, the heart rate then rises continu- chondrial creatine kinase ( B1 and p. 40). The ously ( p. 75 B). The muscles can temporarily CrP reserve of the muscle is sufficient for compensate for the energy deficit (see above), short-term high-performance bursts of but the H+-consuming lactate metabolism can- 10 – 20 s (e.g., for a 100-m sprint). not keep pace with the persistently high level Anaerobic glycolysis occurs later than CrP of anaerobic ATP regeneration. An excess of dephosphorylation (after a maximum of ca. lactate and H+ ions, i.e. lactacidosis, therefore 30 s). In anaerobic glycolysis, muscle glycogen develops. If an individual exceeds his or her is converted via glucose-6-phosphate to lactic endurance limit by around 60%, which is about acid ( lactate + H+), yielding 3 ATP molecules equivalent to maximum O2 consumption for each glucose residue ( B2). During light ( p. 74), the plasma lactate concentration exercise, lactate is broken down in the heart will increase sharply, reaching the so-called and liver whereby H+ ions are used up. Aerobic anaerobic threshold at 4 mmol/L. No significant oxidation of glucose and fatty acids takes place increase in performance can be expected after approx. 1 min after this less productive an- that point. The systemic drop in pH results in aerobic form of ATP regeneration. If aerobic ox- increasing inhibition of the chemical reactions idation does not produce a sufficient supply of needed for muscle contraction. This ultimately ATP during strenuous exercise, anaerobic gly- leads to an ATP deficit, rapid muscle fatigue colysis must also be continued. and, finally, a stoppage of muscle work. CrP metabolism and anaerobic glycolysis In this case, however, glucose must be imported enable the body to achieve three times the per- from the liver where it is formed by glycogenolysis and gluconeogenesis (see also p. 282f.). Imported formance possible with aerobic ATP regenera- glucose yields only two ATP for each molecule of glu- tion, albeit for only about 40 s. However, these cose, because one ATP is required for 6-phosphoryla- processes result in an O2 deficit that must be tion of glucose. compensated for in the post-exercise recovery phase (O2 debt). The body “pays off” this debt Aerobic regeneration of ATP from glucose by regenerating its energy reserves and break- (2 + 34 ATP per glucose residue) or fatty acids is ing down the excess lactate in the liver and required for sustained exercise ( B3). The car- heart. The O2 debt after strenuous exercise is diac output (= heart rate stroke volume) and much larger (up to 20 L) than the O2 deficit for total ventilation must therefore be increased several reasons.72 to meet the increased metabolic requirements of the muscle; the heart rate then becomes Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 85. A. ATP as a direct energy source ADP Pi Reserve enough for 10 contractions Energy Supply for Muscle Contraction Chemical energy Reserve: ATP ∆G ≈ –50 kJ /mol ATP ca. 5 µmol Contraction per g muscle Mechanical Heat + energy B. Regeneration of ATP1 Cleavage of creatine phosphate Reserve: ca. 25 µmol CrP ADP per g muscle Creatine kinase Short-term Cr ATP peak performance Plate 2.17 2 Anaerobic glycolysis Reserve: Glycogen ca. 100 µmol/g muscle Blood Liver glucose Glucose-6-P 1 ATP 1anaerobic ATP Net gain: 2 mol ATP/mol glucose (3 mol ATP/mol glucose-6-P) Long-term high performance 4 ATP Increase in lactic acid Drop in pH 2pyruvic acid 2pyruvate– + 2 H+ Broken down 2 lactic acids 2 H++ 2 lactate– in liver and heart 3 Oxidation of glucose Total net gain: 2 36 mol ATP/mol glucose Acetyl-CoA 6 O2aerobic H2O Krebs 34 6 CO2 ATP Endurance sport cycle Respiratory chain 73 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 86. The smaller the muscle mass involved in the work, Physical Work the higher the increase in blood pressure. Hence, the There are three types of muscle work: blood pressure increase in arm activity (cutting hedges) is higher than that in leg activity (cycling). In ! Positive dynamic work, which requires to patients with coronary artery disease or cere- muscles involved to alternately contract and brovascular sclerosis, arm activity is therefore more relax (e.g., going uphill). dangerous than leg activity due to the risk of myo- ! Negative dynamic work, which requires the cardial infarction or brain hemorrhage. muscles involved to alternately extend while Muscular blood flow. At the maximum work braking (braking work) and contract without a2 Nerve and Muscle, Physical Work level, the blood flow in 1 kg of active muscle load (e.g., going downhill). rises to as much as 2.5 L/min ( p. 213 A), ! Static postural work, which requires con- equivalent to 10% of the maximum cardiac out- tinuous contraction (e.g., standing upright). put. Hence, no more than 10 kg of muscle Many activities involve a combination of two ( 1/3 the total muscle mass) can be fully ac- or three types of muscle work. Outwardly tive at any one time. Vasodilatation, which is directed mechanical work is produced in dy- required for the higher blood flow, is mainly namic muscle activity, but not in purely pos- achieved through local chemical influences tural work. In the latter case, force distance = ( p. 212). In purely postural work, the in- 0. However, chemical energy is still consumed crease in blood flow is prevented in part by the and completely transformed into a form of fact that the continuously contracted muscle heat called maintenance heat (= muscle force squeezes its own vessels. The muscle then times the duration of postural work). fatigues faster than in rhythmic dynamic work. In strenuous exercise, the muscles require up During physical exercise ( C1), the ventila- to 500 times more O2 than when at rest. At the . tion (VE) increases from a resting value of ca. same time, the muscle must rid itself of meta- 7.5 L/min to a maximum of 90 to 120 L/min bolic products such as H+, CO2, and lactate ( C3). Both the respiratory rate (40–60 min– 1 ( p. 72). Muscle work therefore requires max; C2) and the tidal volume (ca. 2 L max.) drastic cardiovascular and respiratory contribute to this increase. Because of the high changes. . VE and increased CO, oxygen consumption In untrained subjects (UT), the cardiac out- . (VO2) can increase from ca. 0.3 L/min at rest to a put (CO; p. 186) rises from 5–6 L/min at rest . maximum (Vo2 max) of ca. 3 L/min in UT ( C4 to a maximum of 15–20 L/min during exercise and p. 76). Around 25 L of air has to be venti- ( p. 77 C). Work-related activation of the lated to take up 1 L of O2 at rest, corresponding sympathetic nervous system increases the . . to a respiratory equivalent (VE/VO2) of 25. heart rate up to ca. 2.5 fold and the stroke . . During physical exercise, VE/VO2 rises beyond volume up to ca. 1.2 fold (UT). In light to mod- the endurance limit to a value of 40–50. erate exercise, the heart rate soon levels out at a Increased O2 extraction in the tissues also new constant level, and no fatigue occurs. Very . contributes to the large increase in VO2 during strenuous exercise, on the other hand, must exercise. The decreasing pH and increasing soon be interrupted because the heart cannot temperature shift the O2 binding curve achieve the required long-term performance towards the right ( p. 129 B). O2 extraction is ( B). The increased CO provides more blood calculated as the arteriovenous difference in for the muscles ( A) and the skin (heat loss; O2 concentration (avDo2 in L/L blood) times the p. 222.). The blood flow in the kidney and in- blood flow in L/min. The maximum O2 con- testine, on the other hand, is reduced by the . sumption (VO2 max) is therefore defined as: sympathetic tone below the resting value . ( A). The systolic blood pressure ( p. 206) VO2 max = HRmax · SVmax · avDO2max rises while the diastolic pressure remains con- where HR is the heart rate and SV is the stroke stant, yielding only a moderate increase in the . volume. VO2 max per body weight is an ideal mean pressure. measure of physical exercise capacity ( p. 76).74 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 87. A. Blood supply in organs at rest and C. Respiration during physical work during physical work 12.5 Physical rest Strenuous work (submaximal)Blood supply (L/min) Exhaustion 400 1 Physical Work Power (W) 200 1.0 0 0 5 10 15 min Plate 2.18 0 CNS Kidney GI tract Muscles 60 Respiration rate (min–1) 2 40 20 0 B. Heart rate during physical work 0 5 10 15 min Total ventilation (L/min) Maximum rate 100 3 200 50 Heart rate (min–1) 150 Strenuous Moderate 0 100 0 5 10 15 min Light 70 6 O2 uptake (L/min) 4 0 4 0 5 10 15 20 25 Time (min) 2 Rest Work Recovery 0 0 5 10 15 min 75 (After J. Stegemann)Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 88. types of physical training strategies, and most Physical Fitness and Training training programs use a combination of them. The physical exercise capacity can be Motor learning, which increases the rate and measured using simple yet standardized tech- accuracy of motor skills (e.g., typewriting). niques of ergometry. This may be desirable in These activities primarily involve the CNS. athletes, for example, to assess the results of Endurance training, which improves sub- training, or in patients undergoing rehabilita- maximal long-term performance (e.g., run- tion therapy. Ergometry assesses the effects of ning a marathon). The main objectives of en- exercise on physiological parameters such as durance training are to increase the oxidative .2 Nerve and Muscle, Physical Work O2 consumption (VO2), respiration rate, heart capacity of slow-twitch motor units ( p. 58!, rate ( p. 74), and the plasma lactate concen- e.g., by increasing the mitochondrial density, tration ( A). The measured physical power increase the cardiac output and, consequently, . (performance) is expressed in watts (W) or to increase VO2 max ( B, C). The resulting in- W/kg body weight (BW). crease in heart weight allows higher stroke volumes ( C) as well as higher tidal volumes, In bicycle ergometry, a brake is used to adjust the watt resulting in very low resting heart rates and level. In “uphill” ergometry on a treadmill set at an angle α, exercise performance in watts is calculated respiratory rates. Trained athletes can there- as a factor of body mass (kg) gravitational accelera- fore achieve larger increases in cardiac output tion g (m · s– 2) distance traveled (m) sin α 1/ and ventilation than untrained subjects ( C). . time required (s– 1). In the Margaria step test, the test The VO2 max of a healthy individual is limited subject is required to run up a staircase as fast as by the cardiovascular capacity, not the respira- possible after a certain starting distance. Perform- tory capacity. In individuals who practice en- ance is then measured as body mass (kg) g durance training, the exercise-related rise in (m · s– 2) height/time (m · s– 1). the lactate concentraton is also lower and oc- Short-term performance tests (10–30 s) curs later than in untrained subjects ( A). measure performance achieved through the Strength training improves the maximum rapidly available energy reserves (creatine short-term performance level (e.g., in weight phosphate, glycogen). Medium-term perform- lifting). The main objectives are to increase the ance tests measure performance fueled by an- muscle mass by increasing the size of the aerobic glycolysis ( p. 72). The maximum O2 muscle fibers (hypertrophy) and to increase . consumption (VO2 max) is used to measure the glycolytic capacity of type motor units longer term aerobic exercise performance ( p. 58). achieved through oxidation of glucose and free Excessive physical exercise causes muscle fatty acids ( p. 74). soreness and stiffness. The underlying cause is In strenuous exercise (roughly 2/3 the max- not lactic acid accumulation, but sarcomere imum physical capacity or more), the aerobic microtrauma, which leads to muscle swelling mechanisms do not produce enough energy, so and pain. The muscle ache, is a sign of micro- anaerobic metabolism must continue as a par- inflammation ( D). allel energy source. This results in lactacidosis Muscle fatigue may be peripheral or central. and a sharp increase in the plasma lactate con- Peripheral fatigue ist caused by the exhaustion centration ( A). Lactate concentrations of of energy reserves and the accumulation of up to 2 mmol/L (aerobic threshold) can be metabolic products in the active muscle. This tolerated for prolonged periods of exercise. is particularly quick to occur during postural Lactate concentrations above 4 mmol/L (an- work ( p. 66). Central fatigue is characterized aerobic threshold) indicate that the perform- by work-related pain in the involved muscles ance limit will soon be reached. Exercise must and joints that prevents the continuation of eventually be interrupted, not because of the physical exercise or decreased the individual’s increasing lactate concentration, but because motivation to continue the exercise. of the increasing level of acidosis ( p. 74). Physical training raises and maintains the76 physical exercise capacity. There are three Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 89. A. Lactate concentration (phys. exercise) B. Maximum O2 uptake · Training-related Oxygen uptake VO2 10 shift (mL/min per kg body weight)Lactate concentration (mmol/L) · Resting VO2 max 8 Women Physical Fitness and Training Non-athletic 2.3 38 6 Anaerobic Athletic 3.3 55 4 threshold Men Aerobic 2 threshold Non-athletic 3.2 44 0 Plate 2.19 0 1 2 3 4 5 Load (W/kg body weight) Athletic 4.8 67 C. Comparison of non-athletic individuals and endurance athletes Physiological parameters Non-athletes Endurance athletes (2 men, age 25, 70 kg) Resting Maximum Resting Maximum (Data partly from H.- J. Ulmer) Heart weight (g) 300 500 Blood volume (L) 5.6 5.9 Heart rate (min-1) 80 180 40 180 Stroke volume (mL) 70 100 140 190 Cardiac output (L/min) 5.6 18 5.6 35 Total ventilation (L/min) 8.0 100 8.0 200 O2 uptake (L/min) 0.3 2.8 0.3 5.2 D. Post-exercise muscle ache Unusually high strain on Cracks in Z disks certain muscles Protein breakdown Water influx Swelling Pain Reduced blood flow Loss of force 77 Several hours later Reflex tension Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 90. 3 Autonomic Nervous System (ANS) Simple reflexes can take place within an Organization of the Autonomic organ (e.g., in the gut, p. 244), but complex Nervous System reflexes are controlled by superordinate auto- In the somatic nervous system, nerve fibers ex- nomic centers in the CNS, primarily in the spi- tend to and from the skeletal muscles, skin and nal cord ( A). These centers are controlled by sense organs. They usually emit impulses in re- the hypothalamus, which incorporates the ANS sponse to stimuli from the outside environ- in the execution of its programs ( p. 330). The ment, as in the withdrawal reflex ( p. 320). cerebral cortex is an even higher-ranking cen- Much somatic nervous activity occurs con- ter that integrates the ANS with other systems. sciously and under voluntary control. In con- The peripheral ANS consists of a sympathetic trast, the autonomic nervous system (ANS) is division and a parasympathetic division ( A) mainly concerned with regulation of circula- which, for the most part, are separate entities tion and internal organs. It responds to chang- ( also p. 80ff.). The autonomic centers of the ing outside conditions by triggering ortho- sympathetic division lie in the thoracic and static responses, work start reactions, etc. to lumbar levels of the spinal cord, and those of regulate the body’s internal environment the parasympathetic division lie in the brain ( p. 2). As the name implies, most activities of stem (eyes, glands, and organs innervated by the ANS are not subject to voluntary control. the vagus nerve) and sacral part of the spinal For the most part, the autonomic and so- cord (bladder, lower parts of the large in- matic nervous systems are anatomically and testine, and genital organs). ( A). Pregan- functionally separate in the periphery ( A), glionic fibers of both divisions of the ANS ex- but closely connected in the central nervous tend from their centers to the ganglia, where system, CNS ( p. 266). The peripheral ANS is they terminate at the postganglionic neurons. efferent, but most of the nerves containing ANS Preganglionic sympathetic neurons arising fibers hold also afferent neurons. These are from the spinal cord terminate either in the called visceral afferents because their signals paravertebral ganglionic chain, in the cervical originate from visceral organs, such as the or abdominal ganglia or in so-called terminal esophagus, gastrointestinal (GI) tract, liver, ganglia. Transmission of stimuli from pregan- lungs, heart, arteries, and urinary bladder. glionic to postganglionic neurons is choliner- Some are also named after the nerve they ac- gic, that is, mediated by release of the neu- company (e.g., vagal afferents). rotransmitter acetylcholine ( p. 82). Stimula- Autonomic nervous activity is usually regu- tion of all effector organs except sweat glands lated by the reflex arc, which has an afferent by the postganglionic sympathetic fibers is limb (visceral and/or somatic afferents) and an adrenergic, i.e., mediated by the release of efferent limb (autonomic and/or somatic effer- norepinephrine ( A and p. 84ff.). ents). The afferent fibers convey stimuli from Parasympathetic ganglia are situated near the skin (e.g. nociceptive stimuli; p. 316) and or within the effector organ. Synaptic trans- nocisensors, mechanosensors and chemosen- missions in the parasympathetic ganglia and sors in organs such as the lungs, gastrointesti- at the effector organ are cholinergic ( A). nal tract, bladder, vascular system and geni- Most organs are innervated by sympathetic tals. The ANS provides the autonomic efferent and parasympathetic nerve fibers. Nonethe- fibers that convey the reflex response to less, the organ’s response to the two systems such afferent information, thereby inducing can be either antagonistic (e.g., in the heart) or smooth muscle contraction ( p. 70) in organs complementary (e.g., in the sex organs). such as the eye, lung, digestive tract and blad- The adrenal medulla is a ganglion and hor- der, and influencing the function of the heart mone gland combined. Preganglionic sympa- ( p. 194) and glands. Examples of somatic thetic fibers in the adrenal medulla release nervous system involvement are afferent acetylcholine, leading to the secretion of epi- stimuli from the skin and sense organs (e.g., nephrine (and some norepinephrine) into the78 light stimuli) and efferent impulses to the bloodstream ( p. 86). skeletal muscles (e.g., coughing and vomiting). Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 91. A. Schematic view of autonomic nervous system (ANS) Controlled Sympathetic division Parasympathetic division (Thoracic and lumbar centers) (Craniosacral centers) by superordinate Transmitter substances: Transmitter substances: Preganglionic: Acetylcholine Preganglionic: Acetylcholine centers Postganglionic: Norepinephrine Postganglionic: Acetylcholine (Exception: Sweat glands, some muscular blood vessels) III VII IX Organization of ANS X Eye α Eye β α Vagus Glands Glands nerve βHeart Heart Plate 3.1 α Bronchi β Blood vessels α Thoracic β Gastrointestinal Smooth muscle tract Liver Pancreas α+β Lumbar Fat and sugar metabolism Ureter Cholinergic Lower colon β Sweat glands α Sacral Urinary Genitals bladder Genitals Urinary bladder Adrenal medulla Cholinoceptors Adrenoceptors: Nicotinic receptors: α Usually excitatory – All postganglionic, (except in GI tract, where autonomic ganglia cells they are indirect relaxants) and dendrites β Usually inhibitory – Adrenal medulla (except in heart, where Muscarinic receptors: they are excitatory) – All target organs innervated β1 mainly in heart by postganglionic para- sympathetic nerve fibers β2 in bronchi, urinary bladder, (and sweat glands innervated uterus, gastrointestinal tract, by sympathetic fibers) etc. 79 Postganglionic: Cholinergic Preganglionic: Cholinergic Postganglionic: Adrenergic Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 92. A. Functions of the autonomic nervous system (ANS) Parasympathetic division (cholinergic) Controlled by Ganglia: NN and M1 receptors superordinate centers Target organ: M2 oder M3 receptors (e.g., hypothalamus) Eye Sphincter pupill. A Ganglion Ganglion sub- Ciliary muscle C ciliare mandibulare3 Autonomic Nervous System (ANS) Lacrimal glands A III Ganglion Submandibular pterygopalatinum VII gland A Chorda tympani Parotid gland A IX Ganglion Cervical Heart oticum X Activation 1 ganglia Slows impulse conduction 2 Kinin release 3 Heart rate 4 Cervical 5 Vasodilatation (sometimes with VIP Bronchi 6 as co-transmitter) Secretion A 7 Musculature C 8 Watery saliva 1 Stomach, intestine 2 (w/o lower colon 3 and rectum) Tone 4 A Sphincter R 5 Secretion A Thoracic 6 7 Gallbladder C 8 9 10 Liver Pancreas 11 Glycogenesis A Exocrine A 12 secretion 1 2 Lumbar 3 Preganglionic Ureter C 4 cholinergic 5 Postganglionic Lower colon, rectum 1 cholinergic Tone A 2 Secretion A Sphincter R 3 4 Sacral Genitals 5 Sympathetic Urinary bladder Erection trunk ganglia Detrusor C Spinal cord (Vasodilatation) Sphincter R80 A = Activation I = Inhibition C = Contraction R = Relaxation D = Dilatation Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 93. Sympathetic division (Preganglionic cholinergic: NN and M1 receptors, postganglionic mainly adrenergic) α receptors (α1: IP3 +DAG ; α2: cAMP ) β receptors (cAMP ) Eye (α1) Eye (β2) Cholinergic C Dilator pupillae Far accommodation of ciliary muscle S A Sweat glands Submandibular Heart (β1 and β2) Functions of ANS gland Faster stimulus Postganglionic conduction sympathetic Mucus secretion Heart rate A (viscous) Myocardial con- traction force Excitability S C Hair muscles Blood vessels of skin D Bronchi (β2) Plate 3.2 u. 3.3 S D Stomach, intestine Stomach, intestine Sympathetic cholinergic Ganglion R Muscle vasodilatation coeliacum C Sphincter (α1) (not confirmed in humans) R Gallbladder Kidney A Renin Pancreas secretion (β1) I Insulin secretion (α2) Pancreas I Exocrine Insulin Adrenal medulla A secretion (β ) secretion 2 A SecretionGanglionmesentericum Blood vesselssup. et inf. C Splenic capsule Skin, muscles, S D etc. S Blood vessels Lipocytes C In skin S Lipolysis Preganglionic In muscles cholinergic Coronaries General Postganglionic Liver (β2 and α1) adrenergic Genitals (α1) Gluconeogenesis Ejaculation Urinary bladder Urinary bladder C Sphincter R Detrusor (β2) Uterus (α1) Uterus (β2) C R (in pregnancy) (Tocolysis) S = Efferents from affiliated CNS segment 81 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 94. different subunits. They are similar in that they Acetylcholine and Cholinergic are both ionotropic receptors, i.e., they act as Transmission cholinoceptors and cation channels at the Acetylcholine (ACh) serves as a neurotransmit- same time. ACh binding leads to rapid Na+ and ter not only at motor end plates ( p. 56) and Ca2+ influx and in early (rapid) excitatory post- in the central nervous system, but also in the synaptic potentials (EPSP; p. 50ff.), which autonomic nervous system, ANS ( p. 78ff.), trigger postsynaptic action potentials (AP) where it is active once they rise above threshold ( A, left ! in all preganglionic fibers of the ANS; panel).3 Autonomic Nervous System (ANS) ! in all parasympathetic postganglionic nerve M-cholinoceptors (M1–M5) indirectly affect endings; synaptic transmission through G-proteins ! and in some sympathetic postganglionic (metabotropic receptors). nerve endings (sweat glands). M1-cholinoceptors occur mainly on auto- nomic ganglia ( A), CNS, and exocrine gland Acetylcholine synthesis. ACh is synthesized in the cytoplasm of nerve terminals, and acetyl coenzyme cells. They activate phospholipase Cβ (PLCβ) A (acetyl-CoA) is synthesized in mitochondria. The via Gq protein in the postganglionic neuron. reaction acetyl-CoA + choline is catalyzed by choline and inositol tris-phosphate (IP3) and diacyl- acetyltransferase, which is synthesized in the soma glycerol (DAG) are released as second mes- and reaches the nerve terminals by axoplasmic trans- sengers ( p. 276) that stimulate Ca2+ influx port ( p. 42). Since choline must be taken up from and a late EPSP ( A, middle panel). Synaptic extracellular fluid by way of a carrier, this is the rate- signal transmission is modulated by the late limiting step of ACh synthesis. EPSP as well as by co-transmitting peptides Acetylcholine release. Vesicles on presynaptic that trigger peptidergic EPSP or IPSP ( A, right nerve terminals empty their contents into the panel). synaptic cleft when the cytosolic Ca2+ concen- M2-cholinoceptors occur in the heart and tration rises in response to incoming action function mainly via a Gi protein ( p. 274 ff.). potentials (AP) ( A, p. 50ff.). Epinephrine and The Gi protein opens specific K+ channels lo- norepinephrine can inhibit ACh release by cated mainly in the sinoatrial node, atri- stimulating presynaptic α2-adrenoceptors oventricular (AV) node, and atrial cells, ( p. 84). In postganglionic parasympathetic thereby exerting negative chronotropic and fibers, ACh blocks its own release by binding to dromotropic effects on the heart ( B). The Gi presynaptic autoreceptors (M-receptors; see protein also inhibits adenylate cyclase, thereby below), as shown in B. reducing Ca2+ influx ( B). ACh binds to postsynaptic cholinergic re- M3-cholinoceptors occur mainly in smooth ceptors or cholinoceptors in autonomic gan- muscles. Similar to M1-cholinoceptors ( A, glia and organs innervated by parasympa- middle panel), M3-cholinoceptors trigger con- thetic fibers, as in the heart, smooth muscles tractions by stimulating Ca2+ influx ( p. 70). (e.g., of the eye, bronchi, ureter, bladder, geni- However, they can also induce relaxation by tals, blood vessels, esophagus, and gastroin- activating Ca2+-dependent NO synthase, e.g., in testinal tract), salivary glands, lacrimal glands, endothelial cells ( p. 278). and (sympathetically innervated) sweat Termination of ACh action is achieved by glands ( p. 80ff.). Cholinoceptors are ni- acetylcholinesterase-mediated cleavage of ACh cotinic (N) or muscarinic (M). N-cholinocep- molecules in the synaptic cleft ( p. 56). Ap- tors (nicotinic) can be stimulated by the alka- proximately 50% of the liberated choline is re- loid nicotine, whereas M-cholinoceptors (mus- absorbed by presynaptic nerve endings ( B). carinic) can be stimulated by the alkaloid Antagonists. Atropine blocks all M-cholino- mushroom poison muscarine. ceptors, whereas pirenzepine selectively Nerve-specific NN-cholinoceptors on auto- blocks M1-cholinoceptors, tubocurarine blocks nomic ganglia ( A) differ from muscle- NM-cholinoceptors ( p. 56), and trimetaphan specific NM-cholinoceptors on motor end blocks NN-cholinoceptors.82 plates ( p. 56) in that they are formed by Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 95. A. Neurotransmission in autonomic ganglia Acetylcholine and Cholinergic Transmission Preganglionic Presynaptic AP neuron ACh Ca2+ Cholinergic NN -receptor Peptide as a co-transmitter Cholinergic Peptide M1-receptor receptor Gq protein PIP K+ Postganglionic Phospholipase C β neuron Na+ (Ca2+) IP3 DAG [Ca]i 20 ms Early EPSP 2s Late EPSP Peptidergic EPSP or IPSP 60 s Plate 3.4 mV mV mV Postsynaptic action potentials B. Cholinergic transmission in the heart Presynaptic AP ACh Postganglionic parasympathetic neuron Ca2+ Choline Cholinergic M-autoreceptor Acetate Acetylcholine Cholinergic esterase M2-receptor K+ channel Adenylyl cyclase Gi protein Gi protein opens Sinus node ATP K+ or AV node cell cAMP Hyperpolarization Sinus node AV node Protein kinase A 0 0 Ca2+ influx mV mV –50 –50 83 Negative chronotropism Negative dromotropismDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 96. α2, β1 and β2) can be distinguished according Catecholamine, Adrenergic to their affinity to E and NE and to numerous Transmission and Adrenoceptors agonists and antagonists. All adrenoceptors re- Certain neurons can enzymatically produce L- spond to E, but NE has little effect on β2- dopa (L-dihydroxyphenylalanine) from the adrenoceptors. Isoproterenol (isoprenaline) amino acid L-tyrosine. L-dopa is the parent activates only β-adrenoceptors, and phen- substance of dopamine, norepinephrine, tolamine only blocks α-adrenoceptors. The ac- and epinephrine—the three natural cate- tivities of all adrenoceptors are mediated by G cholamines, which are enzymatically synthe- proteins ( p. 55).3 Autonomic Nervous System (ANS) sized in this order. Dopamine (DA) is the final Different subtypes (α1 A, α1 B, α1 D) of α1- step of synthesis in neurons containing only adrenoceptors can be distinguished ( B1). the enzyme required for the first step (the aro- Their location and function are as follows: CNS matic L-amino acid decarboxylase). Dopamine (sympathetic activity ), salivary glands, liver is used as a transmitter by the dopaminergic (glycogenolysis ), kidneys (alters threshold neurons in the CNS and by autonomic neurons for renin release; p. 184), and smooth that innervate the kidney. muscles (trigger contractions in the arterioles, Norepinephrine (NE) is produced when a uterus, deferent duct, bronchioles, urinary second enzyme (dopamine-β-hydroxylase) is bladder, gastrointestinal sphincters, and di- also present. In most sympathetic postgan- lator pupillae). glionic nerve endings and noradrenergic central Activation of α1-adrenoceptors ( B1), me- neurons, NE serves as the neurotransmitter diated by Gq proteins and phospholipase Cβ along with the co-transmitters adenosine tri- (PLCβ), leads to formation of the second mes- phosphate (ATP), somatostatin (SIH), or neu- sengers inositol tris-phosphate (IP3), which in- ropeptide Y (NPY). creases the cytosolic Ca2+ concentration, and Within the adrenal medulla (see below) diacylglycerol (DAG), which activates protein and adrenergic neurons of the medulla ob- kinase C (PKC; see also p. 276). Gq protein-me- longata, phenylethanolamine N-methyltrans- diated α1-adrenoceptor activity also activates ferase transforms norepinephrine (NE) into Ca2+-dependent K+ channels. The resulting K+ epinephrine (E). outflow hyperpolarizes and relaxes target The endings of unmyelinated sympathetic smooth muscles, e.g., in the gastrointestinal postganglionic neurons are knobby or varicose tract. ( A). These knobs establish synaptic contact, Three subtypes (α2 A, α2 B, α2 C) of α2-adreno- albeit not always very close, with the effector ceptors ( B2) can be distinguished. Their lo- organ. They also serve as sites of NE synthesis cation and action are as follows: CNS (sympa- and storage. L-tyrosine ( A1) is actively thetic activity , e.g., use of the α2 agonist taken up by the nerve endings and trans- clonidine to lower blood pressure), salivary formed into dopamine. In adrenergic stimula- glands (salivation ), pancreatic islets (insulin tion, this step is accelerated by protein kinase secretion ), lipocytes (lipolysis ), platelets A-mediated (PKA; A2) phosphorylation of (aggregation ), and neurons (presynaptic au- the responsible enzyme. This yields a larger toreceptors, see below). Activated α2-adreno- dopamine supply. Dopamine is transferred to ceptors ( B2) link with Gi protein and inhibit chromaffin vesicles, where it is transformed (via αi subunit of Gi) adenylate cyclase (cAMP into NE ( A3). Norepinephrine, the end prod- synthesis , p. 274) and, at the same time, in- uct, inhibits further dopamine synthesis crease (via the βγ subunit of Gi) the open- (negative feedback). probability of voltage-gated K+ channels (hy- NE release. NE is exocytosed into the synap- perpolarization). When coupled with G0 pro- tic cleft after the arrival of action potentials at teins, activated α2-adrenoceptors also inhibit the nerve terminal and the initiation of Ca2+ in- voltage-gated Ca2+ channels ([Ca2+]i ). flux ( A4 and p. 50). All β-adrenoceptors are coupled with a GS Adrenergic receptors or adrenoceptors protein, and its αS subunit releases cAMP as a84 ( B). Four main types of adrenoceptors (α1, second messenger. cAMP then activates pro- Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 97. A. Adrenergic transmission Activates Adrenal Inhibits medulla Epinephrine (E) L-tyrosine Adrenergic Transmission I Varicosities Bloodstream 1 L-dopa β2-adrenoceptor Inactivated 2 (MAO) 4 cAMP Dopamine Action potential Ca2+ PKA 7 NE NE 6d Plate 3.5 α2 -adrenoceptor α2-adreno- 3 ceptor Heart, glands, smooth muscle 6c 5 6b Inactivated: Re- absorption by MAO by COMT Norepinephrine Epinephrine (NE) Capillary 6a Diffusion into blood (raises NE in blood) α- β- adrenoceptors adrenoceptors α1 α2 β1 β2tein kinase A (PKA), which phosphorylates probability of voltage-gated Ca2+ channels indifferent proteins, depending on the target cell the heart. In the kidney, the basal renin secre-type ( p. 274). tion is increased via β1-adrenoceptors. NE and E work via β1-adrenoceptors ( B3) Activation of β2-adrenoceptors by epineph-to open L-type Ca2+ channels in cardiac cell rine ( B4) increases cAMP levels, therebymembranes. This increases the [Ca2+]i and lowering the [Ca2+]i (by a still unclear mecha-therefore produces positive chronotropic, dro- nism). This dilates the bronchioles and bloodmotropic, and inotropic effects. Activated Gs vessels of skeletal muscles and relaxes theprotein can also directly increase the open- muscles of the uterus, deferent duct, and 85 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 98. gastrointestinal tract. Further effects of β2- In alarm reactions, secretion of E (and some adrenoceptor activation are increased insulin NE) from the adrenal medulla increases sub- secretion and glycogenolysis in liver and stantially in response to physical and mental or muscle and decreased platelet aggregation. Epi- emotional stress. Therefore, cells not sympa- nephrine also enhances NE release in nor- thetically innervated are also activated in such adrenergic fibers by way of presynaptic β2- stress reactions. E also increases neuronal NE adrenoceptors ( A2, A5). release via presynaptic β2-adrenoceptors Heat production is increased via β3-adreno- ( A2). Epinephrine secretion from the ceptors on brown lipocytes ( p. 222). adrenal medulla (mediated by increased sym-3 Autonomic Nervous System (ANS) NE in the synaptic cleft is deactivated by pathetic activity) is stimulated by certain trig- ( A6 a – d): gers, e.g., physical work, cold, heat, anxiety, ! diffusion of NE from the synaptic cleft into anger (stress), pain, oxygen deficiency, or a drop the blood; in blood pressure. In severe hypoglycemia ! extraneuronal NE uptake (in the heart, ( 30 mg/dL), for example, the plasma epi- glands, smooth muscles, glia, and liver), and nephrine concentration can increase by as subsequent intracellular degradation of NE by much as 20-fold, while the norepinephrine catecholamine-O-methyltransferase (COMT) concentration increases by a factor of only 2.5, and monoamine oxidase (MAO); resulting in a corresponding rise in the E/NE ! active re-uptake of NE (70%) by the presyn- ratio. aptic nerve terminal. Some of the absorbed NE The main task of epinephrine is to mobilize enters intracellular vesicles ( A3) and is re- stored chemical energy, e.g., through lipolysis used, and some is inactivated by MAO; and glycogenolysis. Epinephrine enhances the ! stimulation of presynaptic α2-adrenocep- uptake of glucose into skeletal muscle tors (autoreceptors; A 6d, 7) by NE in the ( p. 282) and activates enzymes that accel- synaptic cleft, which inhibits the further re- erate glycolysis and lactate formation lease of NE. ( p. 72ff.). To enhance the blood flow in the Presynaptic α2-adrenoceptors can also be muscles involved, the body increases the car- found on cholinergic nerve endings, e.g., in the diac output while curbing gastrointestinal gastrointestinal tract (motility ) and cardiac blood flow and activity ( p. 75 A). Adrenal ep- atrium (negative dromotropic effect), whereas inephrine and neuronal NE begin to stimulate presynaptic M-cholinoceptors are present on the secretion of hormones responsible for re- noradrenergic nerve terminals. Their mutual plenishing the depleted energy reserves (e.g., interaction permits a certain degree of periph- ACTH; p. 297 A) while the alarm reaction is eral ANS regulation. still in process. Adrenal Medulla Non-cholinergic, Non-adrenergic Transmitters After stimulation of preganglionic sympa- thetic nerve fibers (cholinergic transmission; In humans, gastrin-releasing peptide (GRP) p. 81), 95% of all cells in the adrenal medulla and vasoactive intestinal peptide (VIP) serve as secrete the endocrine hormone epinephrine co-transmitters in preganglionic sympathetic (E) into the blood by exocytosis, and another fibers; neuropeptide Y (NPY) and somatostatin 5% release norepinephrine (NE). Compared to (SIH) are the ones involved in postganglionic noradrenergic neurons (see above), NE synthe- fibers. Postganglionic parasympathetic fibers sis in the adrenal medulla is similar, but most utilize the peptides enkephalin, substance P of the NE leaves the vesicle and is enzymati- (SP) and/or NPY as co-transmitters. cally metabolized into E in the cytoplasm. Modulation of postsynaptic neurons seems Special vesicles called chromaffin bodies then to be the primary goal of preganglionic peptide actively store E and get ready to release it and secretion. There is substantial evidence dem- co-transmitters (enkephalin, neuropeptide Y) onstrating that ATP (adenosine triphosphate),86 by exocytosis. NPY and VIP also function as independent neu- Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 99. B. Adrenoceptors Norepinephrine Natural agonists Epinephrine Agonists: Iso- Salbu- Phenylephrine Clonidine proterenol tamol Adrenergic Transmission II Antagonists: Prazosin Yohimbine Atenolol Adrenergic receptors: 1 2 3 4 α1 α2 β1 β2 Gq Gq Go Gi Gs Gs PIP2 cAMP cAMP PLC β cAMP + K Ca2+ K+ PKA PKA DAG IP3 Plate 3.6 PKA PKC Ca2+ ? Ca2+ Hyper- [Ca2+]i [Ca2+]i Hyper- [Ca2+]i [Ca2+]i polarization polarization Inhibition of gastrointestinal α2 β1 β2 motility α1 Inhibition of exocytosis Drives heart Dilatation of α1 or secretion • Vessels Contraction of • Blood vessels • Salivary glands • Bronchioles • Bronchioles • Insulin • Uterus • Sphincters • Norepinephrine Renin release etc. • Uterus • Acetylcholine etc. etc.rotransmitters in the autonomic nervous sys- nal secretion. Nitric oxide (NO) is liberatedtem. VIP and acetylcholine often occur jointly from nitrergic neurons ( p. 278)(but in separate vesicles) in the parasympa-thetic fibers of blood vessels, exocrine glands,and sweat glands. Within the gastrointestinaltract, VIP (along with nitric oxide) induces theslackening of the circular muscle layer andsphincter muscles and (with the co-transmit-ters dynorphin and galanin) enhances intesti- 87 Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 100. 4 Blood (e.g., heme) can be protected from breakdown Composition and Function of Blood and renal excretion. The binding of small The blood volume of an adult correlates with molecules to plasma proteins reduces their his or her (fat-free) body mass and amounts to osmotic efficacy. Many plasma proteins are in- ca. 4–4.5 L in women (&) and 4.5–5 L in men of volved in blood clotting and fibrinolysis. 70 kg BW ((; table). The functions of blood Serum forms when fibrinogen separates from include the transport of various molecules (O2, plasma in the process of blood clotting. CO2, nutrients, metabolites, vitamins, electro- The formation of blood cells occurs in the red lytes, etc.), heat (regulation of body tempera- bone marrow of flat bone in adults and in the ture) and transmission of signals (hormones) as spleen and liver of the fetus. Hematopoietic tis- well as buffering and immune defense. The sues contain pluripotent stem cells which, with blood consists of a fluid (plasma) formed el- the aid of hematopoietic growth factors (see ements: Red blood cells (RBCs) transport O2 below), develop into myeloid, erythroid and and play an important role in pH regulation. lymphoid precursor cells. Since pluripotent White blood cells (WBCs) can be divided into stem cells are autoreproductive, their existence neutrophilic, eosinophilic and basophilic is ensured throughout life. In lymphocyte granulocytes, monocytes, and lymphocytes. development, lymphocytes arising from lym- Neutrophils play a role in nonspecific immune phoid precursor cells first undergo special defense, whereas monocytes and lymphocytes differentiation (in the thymus or bone marrow) participate in specific immune responses. and are later formed in the spleen and lymph Platelets (thrombocytes) are needed for he- nodes as well as in the bone marrow. All other mostasis. Hematocrit (Hct) is the volume ratio precursor cells are produced by myelocytopoie- of red cells to whole blood ( C and Table). sis, that is, the entire process of proliferation, Plasma is the fluid portion of the blood in maturation, and release into the bloodstream which electrolytes, nutrients, metabolites, vi- occurs in the bone marrow. Two hormones, er- tamins, hormones, gases, and proteins are dis- ythropoietin and thrombopoietin, are involved solved. in myelopoiesis. Thrombopoietin (formed Plasma proteins ( Table) are involved in mainly in the liver) promotes the maturation humoral immune defense and maintain on- and development of megakaryocytes from cotic pressure, which helps to keep the blood which the platelets are split off. A number of volume constant. By binding to plasma pro- other growth factors affect blood cell formation teins, compounds insoluble in water can be in bone marrow via paracrine mechanisms. transported in blood, and many substances Erythropoietin promotes the maturation and proliferation of red blood cells. It is secreted by Blood volume in liters relative to body weight (BW) the liver in the fetus, and chiefly by the kidney ( 0.041 BW (kg) + 1.53, & 0.047 BW (kg) + 0.86 (ca. 90%) in postnatal life. In response to an oxy- Hematocrit (cell volume/ blood volume): gen deficiency (due to high altitudes, hemoly- ( 0.40–0.54 Females: 0.37–0.47 sis, etc.; A), erythropoietin secretion in- Erythrocytes (1012/L of blood = 106/ µL of blood): creases, larger numbers of red blood cells are ( 4.6–5.9 & 4.2–5.4 produced, and the fraction of reticulocytes Hemoglobin (g/L of blood): (young erythrocytes) in the blood rises. The life (140–180 & 120–160 span of a red blood cell is around 120 days. Red MCH, MCV, MCHC—mean corpuscular (MC), hemo- blood cells regularly exit from arterioles in the globin (Hb), MC volume, MC Hb concentration C splenic pulp and travel through small pores to 9 3 Leukocytes (10 /L of blood = 10 / µL of blood): enter the splenic sinus ( B), where old red 3–11 (64% granulocytes, 31% lymphocytes, blood cells are sorted out and destroyed 6% monocytes) (hemolysis). Macrophages in the spleen, liver, 9 3 Platelets (10 /L of blood = 10 / µL of blood): bone marrow, etc. engulf and break down the ( 170–360 &180–400 cell fragments. Heme, the iron-containing88 Plasma proteins (g/L of serum): group of hemoglobin (Hb) released during 66–85 (including 55–64% albumin) hemolysis, is broken down into bilirubin Despopoulos, Color Atlas of Physiology © 2003p. 250), and the iron is recycled ( p. 90). ( Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 101. A. Regulation of RBC production B. Life cycle of red blood cells 1 Hypoxia Bone marrow PO 2 High altitude, etc. RBC formation Composition and Function of Blood PO 2 Kidney Life span: 120 days Erythrocytes Erythropoietin Blood Bone marrow2 Hemolysis Break- PO 2 Hemolysis down Spleen “Still good” Plate 4.1 PO 2 Test “Too old” Spenic Phagocytosis pulp by macrophages in: Pulpal Erythropoietin arteriole Bone marrow Lymph nodes Sinus Spleen Liver, etc. C. Erythrocyte parameters MCH, MCV and MCHC Centrifugation Blood sample a MCH (mean Hb mass/RBC) b Hb conc. = (g/RBC) red cell count Normal: 27 – 32 pg Hematocrit (Hct)= b/a (L RBC/L Blood) MCV (mean volume of one RBC) Hct Hemoglobin concentration = (L/RBC) (g/L BLOOD) red cell count Normal: Red cell count (RCC) 80 –100 fl (quantity/LBLOOD) MCHC (mean Hb conc. in RBCs) Hb conc. = (g/L RBC) Hct Normal: 320 – 360 g/L 89Despopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 102. transferrin receptors. Once iron has been re- Iron Metabolism and Erythropoiesis leased to the target cells, apotransferrin again Roughly 2/3 of the body’s iron pool (ca. 2 g in becomes available for uptake of iron from the women and 5 g in men) is bound to hemoglobin intestine and macrophages (see below). (Hb). About 1/4 exists as stored iron (ferritin, he- Iron storage and recycling ( A3). Ferritin, mosiderin), the rest as functional iron (myoglo- one of the chief forms in which iron is stored in bin, iron-containing enzymes). Iron losses the body, occurs mainly in the intestinal mu- from the body amount to about 1 mg/day in cosa, liver, bone marrow, red blood cells, and men and up to 2 mg/day in women due to plasma. It contains binding pockets for up to menstruation, birth, and pregnancy. Iron ab- 4500 Fe3+ ions and provides rapidly available sorption occurs mainly in the duodenum and stores of iron (ca. 600 mg), whereas iron mobi- varies according to need. The absorption of iron lization from hemosiderin is much slower supplied by the diet usually amounts to about (250 mg Fe in macrophages of the liver and 3 to 15% in healthy individuals, but can in- bone marrow). Hb-Fe and heme-Fe released crease to over 25% in individuals with iron from malformed erythroblasts (so-called in- deficiency ( A1). A minimum daily iron in- efficient erythropoiesis) and hemolyzed red take of at least 10–20 mg/day is therefore rec- blood cells bind to haptoglobin and ommended (women children men). hemopexin, respectively. They are then en- Iron absorption ( A2). Fe(II) supplied by gulfed by macrophages in the bone marrow or the diet (hemoglobin, myoglobin found chiefly in the liver and spleen, respectively, resulting4 Blood in meat and fish) is absorbed relatively effi- in 97% iron recycling ( A3). ciently as a heme-Fe(II) upon protein cleavage. An iron deficiency inhibits Hb synthesis, With the aid of heme oxygenase, Fe in mucosal leading to hypochromic microcytic anemia: cells cleaves from heme and oxidizes to Fe(III). MCH 26 pg, MCV 70 fL, Hb 110 g/L. The The triferric form either remains in the mucosa primary causes are: as a ferritin-Fe(III) complex and returns to the ! blood loss (most common cause); 0.5 mg Fe lumen during cell turnover or enters the are lost with each mL of blood; bloodstream. Non-heme-Fe can only be ab- ! insufficient iron intake or absorption; sorbed as Fe2+. Therefore, non-heme Fe(III) ! increased iron requirement due to growth, must first be reduced to Fe2+ by ferrireductase pregnancy, breast-feeding, etc.; (FR; A2) and ascorbate on the surface of the ! decreased iron recycling (due to chronic in- luminal mucosa ( A2). Fe2+ is probably ab- fection); sorbed through secondary active transport via ! apotransferrin defect (rare cause). an Fe2+-H+ symport carrier (DCT1) (competi- Iron overload most commonly damages the liver, tion with Mn2+, Co2+, Cd2+, etc.). A low chymous pancreas and myocardium (hemochromatosis). If pH is important since it (a) increases the H+ the iron supply bypasses the intestinal tract (iron in- gradient that drives Fe2+ via DCT1 into the cell jection), the transferrin capacity can be exceeded and (b) frees dietary iron from complexes. The and the resulting quantities of free iron can induce absorption of iron into the bloodstream is iron poisoning. regulated by the intestinal mucosa. When an B12 vitamin (cobalamins) and folic acid are also iron deficiency exists, aconitase (an iron-regu- required for erythropoiesis ( B). Deficiencies lating protein) in the cytosol binds with fer- lead to hyperchromic anemia (decreased RCC, ritin-mRNA, thereby inhibiting mucosal fer- increased MCH). The main causes are lack of ritin translation. As a result, larger quantities intrinsic factor (required for cobalamin resorp- of absorbed Fe(II) can enter the bloodstream. tion) and decreased folic acid absorption due Fe(II) in the blood is oxidized to Fe(III) by to malabsorption (see also p. 260) or an ex- ceruloplasmin (and copper). It then binds to tremely unbalanced diet. Because of the large apotransferrin, a protein responsible for iron stores available, decreased cobalamin absorp- transport in plasma ( A2, 3). Transferrin tion does not lead to symptoms of deficiency (= apotransferrin loaded with 2 Fe(III)), is until many years later, whereas folic acid defi-90 taken up by endocytosis into erythroblasts and ciency leads to symptoms within a few cells of the liver, placenta, etc. with the aid of months. Despopoulos, Color Atlas of Physiology © 2003 Thieme All rights reserved. Usage subject to terms and conditions of license.
  • 103. A. Iron intake and metabolism1 Iron intake 2 Fe absorption Mucosal cells Lumen Blood Normal Fe intake: transferrin Heme- (duodenum) 10– 20 mg/day FeII Iron Metabolism and Erythropoiesis 5 –10 mg/day Heme Apo- Fe 2+ III Fe absorption: Fe Fe Mucosal 3 –15 % of FR transferrin HCI Fe Fe intake Fe2+ Ferritin Fe Stomach + H Lyso- FeIII Trans- ferrin Liver some Cell FeIII FeIII turnover FeIII Non-absorbed Fe in feces: Normally 85–97% of intake Plate 4.2 3 Fe storage and Fe recycling Transferrin Fe Bone marrow Liver Systemic blood Ferritin Hemo- Fe Ferritin Fe Heme pexin Hemo- siderin Hapto- Hemo- globin Hb siderin Fe stores Erythrocytes Already in bone marrow Macrophages in spleen, liver and bone marrow (extravascular) B. Folic acid and vitamin B12 (cobalamins) NADP NADPH +H+ Folic acid Other organs Dihydrofolate 0.05mg/day reductase Vitamin B12 0.001mg/day 7, 8- Stores dihydro- 1 mg Methyl- Folate folate cobalamin regeneration Intrinsic factor 7 mg N5-tetra- Tetrahydro- Thymidylate hydrofolate folate synthase Liver Stomach Deoxy- Erythropoiesis Deoxy- uridylate thymidylate Erythrocytes Erythroblast DNA synthesis Ileum 91 Bone marrowDespopoulos, Color Atlas of Physiology © 2003 ThiemeAll rights reserved. Usage subject to terms and conditions of license.
  • 104. molecular weight proteins ( B) as well as Flow Properties of Blood ions and non-charged substances with low The viscosity (η) of blood is higher than that of molecular weights are dissolved in plasma. plasma due to its erythrocyte (RBC) content. The sum of the concentrations of these parti- Viscosity (η) = 1/fluidity = shearing force cles yields a plasma osmolality of 290 mOsm/ (τ)/shearing action (γ) [Pa · s]. The viscosity of kgH2O ( pp. 164, 377). The most abundant blood rises with increasing hematocrit and cation in plasma is Na+, and the most abundant decreasing flow velocity. Erythrocytes lack the anions are Cl– and HCO3–. Although plasma major organelles and, therefore, are highly de- proteins carry a number of anionic net charges formable. Because of the low viscosity of their ( C), their osmotic efficacy is smaller because contents, the liquid film-like characteristics of the number of particles, not the ionic valency, their membrane, and their high surface/ is the determining factor. volume ratio, the blood behaves more like an The fraction of proteins able to leave the emulsion than a cell suspension, especially blood vessels is small and varies from one when it flows rapidly. The viscosity of flowing organ to another. Capillaries in the liver, for ex- blood (ηblood) passing through small arteries ( ample, are much more permeable to proteins 20 µm) is about 4 relative units (RU). This is than those in the brain. The composition of in- twice as high as the viscosity of plasma (ηplasma terstitial fluid therefore differs significantly = 2 RU; water: 1 RU = 0.7 mPa · s at 37 C). from that of plasma, especially with respect to Because they are highly deformable, normal protein content ( C). A completely different4 Blood RBCs normally have no problem passing composition is found in the cytosol, where K+ is through capillaries or pores in the splenic ves- the prevailing cation, and where phosphates, sels (see p. 89 B), although their diameter ( proteins and other organic anions comprise 5 µm) is smaller than that of freely mobile the major fraction of anions ( C). These frac- RBCs (7 µm). Although the slowness of flow in tions vary depending on cell type. small vessels causes the blood viscosity to in- Sixty percent of all plasma protein ( B) is crease, this is partially compensated for albumin (35–46 g/L). Albumin serves as a ve- (ηblood ) by the passage of red cells in single hicle for a number of substances in the blood. file through the center of small vessels (diame- They are the main cause of colloidal osmotic ter 300 µm) due to the Fåhraeus–Lindqvist pressure or, rather, oncotic pressure ( pp. 208, effect ( A). Blood viscosity is only slightly 378), and they provide a protein reserve in higher than plasma viscosity in arterioles times of protein deficiency. The α1, α2 and β ( 7 µm), but rises again in capillaries globulins mainly serve to transport lipids ( 4 µm). A critical increase in blood viscos- (apolipoproteins), hemoglobin (haptoglobin), ity can occur a) if blood flow becomes too slug- iron (apotransferrin), cortisol (transcortin), gish and/or b) if the fluidity of red cells and cobalamins (transcobalamin). Most decreases due to hyperosmolality (resulting in plasma factors for coagulation and fibrinolysis crenation), cell inclusion, hemoglobin malfor- are also proteins. Most plasma immuno- mation (e.g., sickle-cell anemia), changes in globulins (Ig, D) belong to the group of γ the cell membrane (e.g., in old red cells), and so globulins and serve as defense proteins (anti- forth. Under such circumstances, the RBCs un- bodies). IgG, the most abundant immuno- dergo aggregation (rouleaux formation), in- globulin (7–15 g/L), can cross the placental creasing the blood viscosity tremendously (up barrier (maternofetal transmission; D). Each to 1000 RU). This can quickly lead to the cessa- Ig consists of two group-specific, heavy protein tion of blood flow in small vessels ( p. 218). chains (IgG: γ chain, IgA: α chain, IgM: µ chain, IgD: δ chain, IgE: ε chain) and two light protein chains (λ or κ chain) linked by disulfide bo