Human Physiology Part 3


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Human Physiology Part 3

  1. 1. Human physiology part 3Homeostatic Mechanisms and cellular communication(Chapter 7 vander)<br />John Paul L. Oliveros, MD<br />
  2. 2. General Characteristics<br />Homeostasis<br />Denotes the relatively stable conditions of the internal environment <br />Steady State<br />A system in which a particular variable is not changing but energy must be added continuously to maintain this variable constant<br />Setpoint/operating point<br />Steady-state temperature of the thermoregulatory system<br />“Stability of an internal environmental variable is achieved by balancing of inputs and outputs “<br />
  3. 3. General Characteristics<br />Negative-feedback system<br />An increase or decrease in the variable regulated brings about responses that tend to move towards the opposite direction of the original change<br />Most common homeostatic mechanisms in the body<br />e.g. Dec in body temp  responses to inc body temp to original value<br />
  4. 4. General Characteristics<br />Positive-feedback Mechanism<br />Initial disturbance in a system sets off a train of events that increase the disturbance even further<br />Does not favor stability<br />Abruptly displaces a system away from its normal set point<br />e.g. Uterine contractions during labor<br />
  5. 5. General Characteristics<br />“Homeostatic control systems do not maintain complete constancy of the internal environment in the face of continued change in the external environment, but can only minimize changes”<br />As long as the initiating event continues, some change in the regulated variable must persists to serve as a signal to maintain to homeostatic response<br />Error signal: persisting signal needed to inform our body that initiating event is still present and that there is still a need to maintain a response<br />Any regulated variable in the body has a narrow range of normal values <br />The range depends on:<br />magnitude of changes in the external conditions<br />Sensitivity of the responding homeostatic system<br />the more precise the regulating system, the smaller the error signal needed, the narrower the variable range<br />
  6. 6. General Characteristics<br />Reset of set points<br />The values of that the homeostatic control systems are trying to keep relatively constant can be altered<br />e.g. Fever  higher temp is adaptive to fight infection<br />e.g. Decrease serum Iron during infection  to deplete infectious organisms of iron required for it to replicate<br />Set points may also change on a rythmical basis<br />Set points may also change due to clashing demands of different regulatory systems<br />
  7. 7. General Characteristics<br />Feedforward regulation<br />Frequently used in conjunction with negative-feedback systems<br />Anticipates changes in a regulated variable<br />Improves speed of the body’s homeostatic responses<br />Minimizes fluctuations in the level of the variable regulated<br />Reduces deviation from the set-point.<br />e.g. Skin nerve receptors for temp  detects cold weather and activates body’s thermoregulatory systems before actual decrease in body temp<br />
  8. 8. Components of homeostatic control systems<br />Reflexes<br />Local homeostatic responses<br />
  9. 9. Reflexes<br />Reflexes<br />Stimulus response sequence<br />A specific involuntary, unpremeditated, unlearned “built-in” response to a particular stimulus<br />However, it may be learned or acquired, but distinction may not be always clear<br />Reflex arc<br />Pathway mediating a reflex<br />
  10. 10. Reflex Arc<br />Components<br />Stimulus<br />Detectable change in the internal or external environment<br />Receptor<br />Detects the environmental change<br />AKA detector<br />Produces a signal in response to a stimulus<br />Afferent pathway<br />Pathway traveled by the signal to the Integrating center<br />Integrating center<br />Receives signals from many receptors responding to different stimuli<br />Integrates numerous bits of information<br />Output of the integrating center reflects the net effect of the total afferent input<br />Efferent pathway<br />The pathway of information from integrating center and effector<br />Effector<br />A device whose change in activity constitutes overall response of the system<br />
  11. 11. Reflexes<br />
  12. 12. Reflexes<br />All body cells act as an effector in homeostatic reflex<br />2 major classes of effector tissues:<br />Muscles<br />glands<br />2 Reflex systems<br />Nervous system<br />e.g. Thermoregulatory reflex<br />Endocrine system<br />Glands: <br />integrating center<br />receptor<br />Hormones<br />Blood borne chemical messenger<br />May serve as an efferent pathway<br />
  13. 13. Local Homeostatic Response<br />Local homeostatic response<br />Another group of biological responses of great importance for homeostasis<br />Initiated by a change in the internal or external environment (stimulus)<br />Induces alteration in cell activity with the net effect of counter acting the stimulus<br />Local response is the result of sequence of events proceeding from a stimulus<br />However, the entire sequence of events occurs only in the area of the stimulus<br />Provide individual areas of the body with mechanisms for local self regulation<br />e.g. Skin damage  local cellular release of protective chemicals<br />
  14. 14. Intercellular Chemical Messengers<br />Vast majority of communiction between cells is performed by chemical messengers<br />Intercellular communication is essential for reflexes, local homeostatic response and therefore to homeostasis<br />3 categories of chemical messengers<br />Hormones<br />Neurotransmitters<br />Paracrine agents<br />
  15. 15. Intercellular Chemical Messengers<br />Hormone<br />Enables the hormone secreting cell to act on its target cell<br />Delivered by blood<br />Neurotransmitter<br />Chemical messengers secreted by nerve cells<br />Released from nerve cell endings and diffuses into the ECF in between nerves/cells to act upon the 2nd Nerve cell or effector cell<br />Neurohormones<br />Nerve cell secretions that enter the bloodstream to act on cells elsewhere in the body<br />
  16. 16. Intercellular Chemical Messengers<br />Paracrine Agents<br />Synthesize by cells and released to the ECF in presence of a stimulus<br />Diffuse into the neighboring target cells<br />Inactivated rapidly by locally existing enzymes<br />Do not enter the blood stream in large quantities<br />Autocrine Agents<br />Chemical secreted by a cell acts on the same cell<br />Frequently, chemical messengers may act as paracrine or autocrine agents<br />Seemingly endless list of paracrine and autocrine agents identified<br />Nitric Oxide<br />Fatty acid derivatives<br />Peptides and AA derivatives<br />Growth factors<br />Etc., etc.<br />Stimuli for release are extremely varried<br />Local chemical changes (e.g change in O2 levels)<br />Neurotransmitters<br />hormones<br />
  17. 17. Intercellular Chemical Messengers<br />Eicosanoids<br />Paracrine/autocrine agents that exert a wide variety of effects in virtually every tissue and organ system<br />A family of substances produced from arachidonic acid<br />Polyunsaturated FA<br />Present in PM phospholipids<br />Groups:<br />Cyclic endoperoxides<br />Prostaglandins<br />Thromboxanes<br />leukotrienes<br />
  18. 18. Intercellular Chemical Messengers<br />Eicosanoids<br />Beyond Phospholipase A2, the eicosanoid pathway found in a particular cell determine which eicosanoids the cell synthesizes in response to a stimulus<br />Each major eicosanoid subdivision has more than 1 member<br />Structural molecular difference designated by a letter (e.g. PGA, PGE)<br />Further subdivisions by number subscripts (PGE2, PGE3)<br />Once synthesized in response to a stimulus, they are immediately released and act locally<br />Drugs that influence eicosanoid pathway<br />Aspirin: <br />Inhibits cyclooxygenase<br />Blocks the synthesis of endoperoxides, prostaglandins and thromboxanes<br />NSAIDs:<br />Also blocks cyclooxygenase<br />Reduce pain, fever, inflammation<br />Adrenal Steroids:<br />Used in large doses<br />Inhibits phospholipaseA2<br />Block production of all eioosanoids<br />
  19. 19. Processes Related to Homeostasis<br />Acclimatization<br />Biological rhythms<br />Regulated Cell Death: Apoptosis<br />Aging<br />Balance in the homeostasis of chemicals<br />
  20. 20. Acclimatization<br />Adaptation:<br />Denotes a characteristic that favors survival in specific environments<br />Homeostatic control systems are inherited biological adaptations<br />Acclimatization:<br />A type of adaptation in which there is an improved functioning of an already existing homeostatic system<br />An individual response to a particular environmental stress is enhanced without a change in genetic endowment<br />Due to prolonged exposure to stress<br />e.g. Sauna bath <br /> 1st day : 30 min<br />1 week : 1-2 hrs/day<br />8th day: earlier sweating, more profuse sweating, body temp does’t rise as much<br />Usually completely reversible<br />Once stress is removed, body reverts back to preacclimatization condition<br />Developmental acclimatization:<br />Acclimatization is induced early in life (critical period) and becomes irreversible<br />
  21. 21. Biological Rhythms<br />Circadian rhythm<br />Most common type<br />Cycles approximately every 24 hrs<br />Body functions<br />Waking and sleeping<br />Body temperature<br />Hormone concentrations<br />Excretion of ions in urine<br />Etc.<br />
  22. 22. Biological Rhythms<br />Add another anticipatory component to homeostatic control systems<br />Act as a feed-forward system operating without detectors<br />Enable homeostatic mechanisms to be utilized immediately and automatically <br />activation at times when a challenge is more likely to occur but before it actually does occur<br />e.g. Decrease urinary K+ excretion at night<br />Entrainment:<br />Setting of the actual hours by the body with timing cues provided by environmental factors<br />e.g. Experiment done on chambers with time to ‘lights off” controlled  wake-sleep cycled persisted but at 25 hrs cycle (free-running rhythm)<br />Environmental cues:<br />Light-Dark cycle: most important environmental cue<br />External environmental temp<br />Meal timing<br />Many social cues<br />
  23. 23. Biological Rhythms<br />Phase shift rhythms<br />Reset of the internal clock by environmental time cues<br />Jet lag<br />Happens when one jets from east or west to a different time zone<br />Sleep-wake cycle and other circadian rhythms slowly shift to the new light-dark cycle<br />Symptoms may be caused by disparity between external time and internal time<br />Symptoms: disruption of sleep, gastrointestinal disturbances, decreased vigilance and attention span, general feeling of malaise<br />
  24. 24. Biological Rhythms<br />Neural basis of body rhythms<br />Suprachiasmatic nucleus<br />A collection of nerve cells in the hypothalamus<br />Functions as the principal pacemaker (time clock) for circadian rhythms<br />Probably involves the rhythmical turning on and off of critical genes in the pacemaker cells<br />Input: from eyes and many parts of the nervous system<br />Output: other parts of the brain<br />Pineal Gland: <br />One of the outputs of the pacemaker<br />Secretes melatonin (usually at night)<br />
  25. 25. Biological Rhythms<br />Have different effects on the body’s resistance to various stresses and responses to different drugs<br />Heart attack: 2x in the first hours of waking<br />Asthma: usually at night<br />Asthma meds: usually given at night to deliver a high dose of med between 12am-6am<br />
  26. 26. Apoptosis<br />Regulated cell death<br />The ability to self-destruct by activation of an intrinsic cell suicide program<br />Important role in the sculpting of a developing organismand in the elimination of undesirable cells (e.g. Cancerous cells)<br />Regulation of the number of cells in tissues and organs<br />Balance between cell proliferation and cell death<br />e.g. Neutrophils die by apoptosis 24 hrs after being produced in the BM<br />
  27. 27. Apoptosis<br />Occurs by controlled autodigestion of cell contents<br />Endogenous enzymesbreakdown nucleus and DNA breakdown of organelles<br />Plasma membrane intact to contain cell contents<br />Signal sent to nearby phagocytes  eat dying cells<br />Toxic breakdown products are contained  no inflammatory response triggered<br />Necrosis: cell death due to injury  release of toxic cell contents  inflammatory response<br />All cells contain apoptopic enzymes maintained inactive by chemical survival signals sent by neighboring cells, hormones, and extracellular matrix<br />
  28. 28. Apoptosis<br />Abnormal inhibition of Apoptosis: <br />cancer<br />Abnormal high rate of apoptosis: <br />degenerative disease (e.g. Osteoporosis)<br />
  29. 29. Aging<br />Physiologic manifestations:<br />Gradual detrioration in the function of virtually all tissues and organs systems<br />Deterioration of the homeostatic control systems to respond to environmental stresses<br />Decrease in the number of cells in the body<br />Decreased cell division<br />Increase cell death<br />Malfunction of remaining cells<br />Immediate cause: Interference in the function of the cells macromolecules (e.g. DNA)<br />
  30. 30. Aging<br />Decreased cell division<br />Built in limit to the number of times a cell divides<br />DNA loses a portion of its terminal segment (telomere) each time it replicates<br />Genetic and environmental factors<br />Progressive damage <br />Variability of lifespan:<br />1/3- genes<br />2/3- differing environments<br />
  31. 31. Aging<br />Genes <br />Probably those that code for proteins that regulate the processes of cellular and macromolecular maintenance and repair<br />Werner’s syndrome: premature aging due to a mutation of a single gene that is critical for DNA replication or repair<br />Difficulty in determining if changes in the body are due to aging or disease<br />Can the aging process be inhibited or slowed down?<br />Exerise<br />Balanced diet: reduces formation of free radicals<br />
  32. 32. Balance in the Homeostasis of Chemicals<br />Balance diagram for a chemical substance<br />
  33. 33. Balance in the Homeostasis of Chemicals<br />Exception to scheme: mineral electrolytes<br />Can’t be synthesized<br />Do not normally enter thru lungs<br />Can’t be removed by metabolism<br />e.g. Na+<br />Generalizations of the balance concept:<br />During any period of time, total-body balance depends upon the relative rates of net gain and net loss to the body<br />The pool concentration depends not only upon the total amount of the substance in the body, but also upon exchanges of the substance within the body<br />
  34. 34. Balance in the Homeostasis of Chemicals<br />3 states of total-body balance <br />Negative balance: <br />Loss exceeds gain <br />amount of substance in the body is decreasing<br />Positive balance: <br />gain exceeds loss,<br />amount in body increasing<br />Stable balance: gain = loss<br />A stable balance can be upset by alteration of the amount being gained or lost in a single pathway in the schema<br />
  35. 35. Section B: Mechanisms by which chemical messengers control cells<br />Homeostatic Mechanisms and Cellular Communication <br />
  36. 36. Receptors<br />Chemical Proteins: ligands<br />Receptors: <br />target cell proteins<br />Binding site<br />Glycoproteins located<br />Plasma membrane<br />More common<br />Transmembrane CHONs<br />Has segments extracellular, within the membrane, and intracellular<br />Where lipid-insoluble messengers bind<br />Intracellular<br />Mainly in the nucleus<br />Where lipid soluble chemical messengers bind<br />
  37. 37. Receptors<br />Specificity:<br />A very important characteristic of Intercellular communication<br />Cells differ in types of receptors they contain<br />Frequently, just one cell type possesses the receptor required for the combination with a given chemical messenger<br />“superfamilies” : group of receptors closely related structurally for a group of messengers<br />
  38. 38. Receptors<br />Different cell types may possess the same receptors for a particular messenger, but responses to the same messenger may differ<br />Receptor functions as a molecular switch that switches on when a messenger binds to it<br />e.g. Norephinephrine<br />Smooth muscle of blood vessel contract<br />Pancreas  decrease insulin secretion<br />A single cell may contain several different receptor types for a single messenger<br />Response different from one receptor to another in the same cell<br />e.g. 2 epinephrine receptor sites in smooth muscle cells of BV (contraction vs dilation)<br />The degree to which the molecules of a messenger bind to different receptor sites in a single cel depends on the affinity of the different receptor types for the messenger<br />
  39. 39. Receptors<br />A single cell contains many different receptors for different chemical messengers<br />Saturation: <br />response increases as extracellular concentration of the messener increases<br />Upper limit to responsiveness due to finite number of receptors available that become saturated at a point<br />Competition:<br />Ability of different messenger molecules that are very similar in structure to compete with each other for a receptor<br />Antagonist:<br /> drugs that bind on the receptors without activatng them<br />prevent messengers from binding and triggering a response<br />e..g. B-blockers<br />
  40. 40. Receptors<br />Agonist:<br />Drugs that bind on a particular receptor and trigger the cell’s response as if a true chemical messenger had combined with the receptor<br />e.g. Ephidrine  epinephrine receptors<br />Down-regulation: <br />High ECF messenger concentration  target cell receptors decrease<br />Reduces target cells’ responsiveness to frequent or intense stimulation by a messenger<br />Local negative feedback mechanism<br />e.g. Insulin  glucose uptake  decrease insulin receptors<br />Up-regulation:<br />Cells exposed to a prolongd period of very low concentrations of a messenger maydevelop many more receptors for the messenger<br />e.g. Denervated muscls contract when injected with small amounts of neurotransmitter<br />
  41. 41. Receptors<br />Down-regulation<br />Binding of messengers to receptors endocytosis  degradation of receptors<br />Up-regulation<br />Stores of receptors in IC vessicles insertion via exocytosis<br />Gene that code for receptors<br />Alteration of expression during down/up-regulation<br />Receptors may decrease or increase due to a disease process<br />Myasthenia gavis: aceylcholine receptors in muscles are destroyed mscle weakness/destruction<br />
  42. 42. Signal Transduction Pathways<br />The sequences of events between receptor activation and the cell’s response<br />Signal:<br />Receptor activation<br />Transduction:<br />Process in which stimulus is transformed into a response<br />Lipid-soluble messengers:<br />Receptors inside the cell<br />Lipid-insoluble messengers<br />Receptors in the plasma membrane of cell<br />
  43. 43. Signal Transduction pathways<br />Receptor activation:<br />Initial step leading to the cell’s ultimate responses to the messenger<br />Causes a change in the conformation of the receptor<br />Common denominator: all directly due to alterations of a particular cell protein<br />Changes may be in the form of:<br />Permeability, transport properties, or electrical state of the plasma membrane<br />The cell’s metabolism<br />The cell’s secretory activity<br />The cell’s rate of proliferation and differentiation<br />Cell’s contractile activity<br />
  44. 44. Signal Transduction Pathways<br />Pathways initiated by intracellular pathways<br />Lipid soluble messengers<br /> mostly hormones<br />Closely related structurally<br />Receptors <br />Steroid hormone receptor superfamily<br />Intracellular, mostly in the nucleus<br />Inactive when not bound to messenger<br />Activation altered rates og gene transcription<br />Transcription Factor<br />Receptor + Hormone<br />Regulatory protein that directly influences gene transcription<br />Response element: <br />specific sequence near a gene in DNA where the receptor binds<br />Increases the rate of the gene’s transcription into mRNA<br />mRNA direct synthesis of CHON encoded by the gene<br />One gene may be subject to control by a single receptor<br />In some cases, transcription of the gene/s is decreased by the activated receptor<br />
  45. 45. Signal Transduction Pathway<br />
  46. 46. Signal Transduction Pathway<br />Pathways initiated by Plasma membrane receptors<br />First messengers<br />Intercellular chemical messenger<br />Hormones, neurotransmitters, paracrine agents<br />Second messengers<br />Non protein substance/enzymatically generated  cytoplasmtransmit signals<br />Protein kinase<br />Any enzyme that phosphorylates other CHONs by transfering them a PO4 group from ATP<br />Changes the activity and sonformation of the CHON<br />May involve may CHON kinase <br />
  47. 47. Signal Transduction Pathway<br />Receptors that Function as ion channels<br />Receptor constitute an ion channel<br />Activation  opening of channels  diffusion of specific channels change in membrane potential cell’s response<br />Ca++ channel  increase cytostolic Ca++ conc.  essential for signal transduction pathways<br />
  48. 48. Signal Transduction Pathways<br />Receptors that function as enzymes<br />With intrinsic enzyme activity<br />Almost all are protein-kinases, mostly tyrosine-kinases<br />Binding of messenger  change in receptor conformation  activation of enzymatic portionautophosphorylation of tyrosine groups  phosphotyrosine “docking sites” for other CHONs  Cascade of signaling pathways within the cell<br />Guanylyl cyclase receptor:<br />Catalyzes formation of cGMP (2nd messenger)  activation of cGMP-dependent protein kinase  phosphorylation of a CHON  cell’s response<br />
  49. 49. Signal Transduction Pathways<br />Receptors that interact with Cytoplasmic JAK Kinases<br />Receptor with intrinsic enzmatic activity<br />Enzymatic activity on receptor’s tyrosine kinase and on separate cytoplasmic kinases (JAK kinases)bound to the receptor<br />Receptor and JAK kinase: function as a unit<br />Messenger  receptor  activation of JAK kinase  phoshorylation of CHONs  transcription factors  synthesis of new CHONs that mediate cell’s response<br />
  50. 50. Signal Transduction Pathways<br />Receptors that interact with G proteins<br />Largest group of receptors<br />G-proteins on the cytoplasm is bound to the receptors<br />Messenger  receptor conformational change  1 of 3 subunits of G-proteins link with plasma membrane effector proteins  sequence of events  cell’s response<br />G-proteins: serve as a switch to couple a receptor with an ion channel or an enzyme in plasma membrane<br />
  51. 51. Signal Transduction Pathway<br />Effector Protein Enzymes:<br />Adenylyl cyclase and Cyclic AMP<br />Phospholipase C, diacylglycerol, and Inositol Triphosphate<br />
  52. 52. Signal Transduction Pathway<br />Adenylyl cyclase and cyclic AMP<br />Messenger  receptor  activation of G protein  activation of Adenylyl Cyclase  conversion of ATP  cAMP (2nd messenger) sequence of events  cell’s response<br />Phosphodiesterase: enzyme that breaks down cAMP to non cyclic AMP, thus termination of its action<br />cAMP  activation cAMP dependent protein kinase (Protein-kinase A)  phosphorylation of proteins  cell response<br />Amplification: 1 active adenylyl cyclase  catalyzation of > 100 cAMP molecules<br />cAMP dependent protein kinase can phosphorylate large number of different proteins  exert multiple actions on a cell<br />cAMP dependent protein kinase may inhibit other enzymes<br />
  53. 53. Signal Transduction Pathway<br />
  54. 54. Signal Transduction Pathways<br />
  55. 55. Signal Transduction Pathways<br />
  56. 56. SignalTransduction Pathways<br />Phospholipase C, Diacylglycerol, and Inositol Triphosphate<br />Gq phospholipase C  breakdown of PIP2  DAG and IP3  different sequence cascade  cell response<br />DAG  activates protein kinase C  phosphorylation of many proteins  cell response<br />IP3  enters cytosol  binds wiith Ca++ channels in Endoplasmic reticulum opening of Ca++ channels  Ca++ diffuses from ER to cytosol  increase cytostolic CA++  sequence of events  cell response<br />
  57. 57. Signal Transduction Pathways<br />
  58. 58. Signal Transduction Pathways<br />Control of ions by G Proteins<br />Direct G-protein gating (fig 7-13d)<br />G-protein interacts directly with ion channels in PM<br />All events occur in the plasma membrane <br />No 2nd messengers involved<br />Indirect G-protein gating (fig 7-17)<br />Utilizes a 2nd messenger <br />
  59. 59. Signal Transduction Pathways<br />Ca++ ion as a 2nd messenger<br />Ca++ is maintained extremely low in cytosol<br />Large electrochemical gradient favoring diffusion of Ca++ via channels in both PM and ER<br />Stimulus: change cytostolic Ca++ levels<br />Active transport systems<br />Ion channels<br />Ca++ channels openingChemical stimuliElectrical gradient<br />Ca++ (2nd messenger)  bind channels in ER opening of channels  release of Ca++ from ER ( calcium-induced calcium release)<br />2nd messenger<br />IP3<br />Ca++<br />
  60. 60. Signal Transduction Pathways<br />Ca++ ions as 2nd messenger<br />Ca++ can bind with various CHONs <br />Ca++ binding alters CHON conformation and activates their function<br />Calmodulin + Ca++  change in shape activation/inhibition of protein kinases<br />Calmodulin –dependent protein kinase activation/inibition  phosphorylation  activation/inibition of CHONs  cell response<br />
  61. 61. Signal Transuction Pathways<br />
  62. 62. Signal Transduction Pathways<br />Receptors and Gene Transcription<br />Plasma membrane receptors: transduction pathways activate Intracellular transcription factors using 2nd messengers<br />Primary Response Genes: <br />Genes with transcription factors activated by first messenger<br />Proteins encoded by PRGs may itself be a transcription factor for another gene<br />
  63. 63. Signal Transduction Pathways<br />Cessation of activity in signal transduction<br />Key event: cessation of receptor activation<br />Decrease in the concentration of the first messenger molecules in the region of the receptor<br />Metabolism by enzymes in the vicinity<br />Uptake by adjacent cells<br />Diffusion away <br />Chemical alteration of the receptor (usually by phosphorylation)<br />Lower affinity for the 1st messenger<br />Release of the messenger<br />Removal of plasma membrane receptor and its endocytosis<br />
  64. 64. Signal Transduction Pathways<br />