Homeostatic mechanisms work to maintain steady internal conditions in the body. They utilize negative feedback systems to counteract changes and return to the normal setpoint. Homeostasis involves reflexes, local responses, and chemical messengers like hormones and neurotransmitters. Receptors on cells detect messengers and trigger signal transduction pathways, ultimately causing cellular responses. This maintains balance and stability within the body.

1. Human physiology part 3Homeostatic Mechanisms and cellular communication(Chapter 7 vander) John Paul L. Oliveros, MD

2. General Characteristics Homeostasis Denotes the relatively stable conditions of the internal environment Steady State A system in which a particular variable is not changing but energy must be added continuously to maintain this variable constant Setpoint/operating point Steady-state temperature of the thermoregulatory system “Stability of an internal environmental variable is achieved by balancing of inputs and outputs “

3. General Characteristics Negative-feedback system An increase or decrease in the variable regulated brings about responses that tend to move towards the opposite direction of the original change Most common homeostatic mechanisms in the body e.g. Dec in body temp  responses to inc body temp to original value

4. General Characteristics Positive-feedback Mechanism Initial disturbance in a system sets off a train of events that increase the disturbance even further Does not favor stability Abruptly displaces a system away from its normal set point e.g. Uterine contractions during labor

5. General Characteristics “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” 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 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 Any regulated variable in the body has a narrow range of normal values The range depends on: magnitude of changes in the external conditions Sensitivity of the responding homeostatic system the more precise the regulating system, the smaller the error signal needed, the narrower the variable range

6. General Characteristics Reset of set points The values of that the homeostatic control systems are trying to keep relatively constant can be altered e.g. Fever  higher temp is adaptive to fight infection e.g. Decrease serum Iron during infection  to deplete infectious organisms of iron required for it to replicate Set points may also change on a rythmical basis Set points may also change due to clashing demands of different regulatory systems

7. General Characteristics Feedforward regulation Frequently used in conjunction with negative-feedback systems Anticipates changes in a regulated variable Improves speed of the body’s homeostatic responses Minimizes fluctuations in the level of the variable regulated Reduces deviation from the set-point. e.g. Skin nerve receptors for temp  detects cold weather and activates body’s thermoregulatory systems before actual decrease in body temp

8. Components of homeostatic control systems Reflexes Local homeostatic responses

9. Reflexes Reflexes Stimulus response sequence A specific involuntary, unpremeditated, unlearned “built-in” response to a particular stimulus However, it may be learned or acquired, but distinction may not be always clear Reflex arc Pathway mediating a reflex

10. Reflex Arc Components Stimulus Detectable change in the internal or external environment Receptor Detects the environmental change AKA detector Produces a signal in response to a stimulus Afferent pathway Pathway traveled by the signal to the Integrating center Integrating center Receives signals from many receptors responding to different stimuli Integrates numerous bits of information Output of the integrating center reflects the net effect of the total afferent input Efferent pathway The pathway of information from integrating center and effector Effector A device whose change in activity constitutes overall response of the system

11. Reflexes

12. Reflexes All body cells act as an effector in homeostatic reflex 2 major classes of effector tissues: Muscles glands 2 Reflex systems Nervous system e.g. Thermoregulatory reflex Endocrine system Glands: integrating center receptor Hormones Blood borne chemical messenger May serve as an efferent pathway

13. Local Homeostatic Response Local homeostatic response Another group of biological responses of great importance for homeostasis Initiated by a change in the internal or external environment (stimulus) Induces alteration in cell activity with the net effect of counter acting the stimulus Local response is the result of sequence of events proceeding from a stimulus However, the entire sequence of events occurs only in the area of the stimulus Provide individual areas of the body with mechanisms for local self regulation e.g. Skin damage  local cellular release of protective chemicals

14. Intercellular Chemical Messengers Vast majority of communiction between cells is performed by chemical messengers Intercellular communication is essential for reflexes, local homeostatic response and therefore to homeostasis 3 categories of chemical messengers Hormones Neurotransmitters Paracrine agents

15. Intercellular Chemical Messengers Hormone Enables the hormone secreting cell to act on its target cell Delivered by blood Neurotransmitter Chemical messengers secreted by nerve cells Released from nerve cell endings and diffuses into the ECF in between nerves/cells to act upon the 2nd Nerve cell or effector cell Neurohormones Nerve cell secretions that enter the bloodstream to act on cells elsewhere in the body

16. Intercellular Chemical Messengers Paracrine Agents Synthesize by cells and released to the ECF in presence of a stimulus Diffuse into the neighboring target cells Inactivated rapidly by locally existing enzymes Do not enter the blood stream in large quantities Autocrine Agents Chemical secreted by a cell acts on the same cell Frequently, chemical messengers may act as paracrine or autocrine agents Seemingly endless list of paracrine and autocrine agents identified Nitric Oxide Fatty acid derivatives Peptides and AA derivatives Growth factors Etc., etc. Stimuli for release are extremely varried Local chemical changes (e.g change in O2 levels) Neurotransmitters hormones

17. Intercellular Chemical Messengers Eicosanoids Paracrine/autocrine agents that exert a wide variety of effects in virtually every tissue and organ system A family of substances produced from arachidonic acid Polyunsaturated FA Present in PM phospholipids Groups: Cyclic endoperoxides Prostaglandins Thromboxanes leukotrienes

18. Intercellular Chemical Messengers Eicosanoids Beyond Phospholipase A2, the eicosanoid pathway found in a particular cell determine which eicosanoids the cell synthesizes in response to a stimulus Each major eicosanoid subdivision has more than 1 member Structural molecular difference designated by a letter (e.g. PGA, PGE) Further subdivisions by number subscripts (PGE2, PGE3) Once synthesized in response to a stimulus, they are immediately released and act locally Drugs that influence eicosanoid pathway Aspirin: Inhibits cyclooxygenase Blocks the synthesis of endoperoxides, prostaglandins and thromboxanes NSAIDs: Also blocks cyclooxygenase Reduce pain, fever, inflammation Adrenal Steroids: Used in large doses Inhibits phospholipaseA2 Block production of all eioosanoids

19. Processes Related to Homeostasis Acclimatization Biological rhythms Regulated Cell Death: Apoptosis Aging Balance in the homeostasis of chemicals

20. Acclimatization Adaptation: Denotes a characteristic that favors survival in specific environments Homeostatic control systems are inherited biological adaptations Acclimatization: A type of adaptation in which there is an improved functioning of an already existing homeostatic system An individual response to a particular environmental stress is enhanced without a change in genetic endowment Due to prolonged exposure to stress e.g. Sauna bath 1st day : 30 min 1 week : 1-2 hrs/day 8th day: earlier sweating, more profuse sweating, body temp does’t rise as much Usually completely reversible Once stress is removed, body reverts back to preacclimatization condition Developmental acclimatization: Acclimatization is induced early in life (critical period) and becomes irreversible

21. Biological Rhythms Circadian rhythm Most common type Cycles approximately every 24 hrs Body functions Waking and sleeping Body temperature Hormone concentrations Excretion of ions in urine Etc.

22. Biological Rhythms Add another anticipatory component to homeostatic control systems Act as a feed-forward system operating without detectors Enable homeostatic mechanisms to be utilized immediately and automatically activation at times when a challenge is more likely to occur but before it actually does occur e.g. Decrease urinary K+ excretion at night Entrainment: Setting of the actual hours by the body with timing cues provided by environmental factors e.g. Experiment done on chambers with time to ‘lights off” controlled  wake-sleep cycled persisted but at 25 hrs cycle (free-running rhythm) Environmental cues: Light-Dark cycle: most important environmental cue External environmental temp Meal timing Many social cues

23. Biological Rhythms Phase shift rhythms Reset of the internal clock by environmental time cues Jet lag Happens when one jets from east or west to a different time zone Sleep-wake cycle and other circadian rhythms slowly shift to the new light-dark cycle Symptoms may be caused by disparity between external time and internal time Symptoms: disruption of sleep, gastrointestinal disturbances, decreased vigilance and attention span, general feeling of malaise

24. Biological Rhythms Neural basis of body rhythms Suprachiasmatic nucleus A collection of nerve cells in the hypothalamus Functions as the principal pacemaker (time clock) for circadian rhythms Probably involves the rhythmical turning on and off of critical genes in the pacemaker cells Input: from eyes and many parts of the nervous system Output: other parts of the brain Pineal Gland: One of the outputs of the pacemaker Secretes melatonin (usually at night)

25. Biological Rhythms Have different effects on the body’s resistance to various stresses and responses to different drugs Heart attack: 2x in the first hours of waking Asthma: usually at night Asthma meds: usually given at night to deliver a high dose of med between 12am-6am

26. Apoptosis Regulated cell death The ability to self-destruct by activation of an intrinsic cell suicide program Important role in the sculpting of a developing organismand in the elimination of undesirable cells (e.g. Cancerous cells) Regulation of the number of cells in tissues and organs Balance between cell proliferation and cell death e.g. Neutrophils die by apoptosis 24 hrs after being produced in the BM

27. Apoptosis Occurs by controlled autodigestion of cell contents Endogenous enzymesbreakdown nucleus and DNA breakdown of organelles Plasma membrane intact to contain cell contents Signal sent to nearby phagocytes  eat dying cells Toxic breakdown products are contained  no inflammatory response triggered Necrosis: cell death due to injury  release of toxic cell contents  inflammatory response All cells contain apoptopic enzymes maintained inactive by chemical survival signals sent by neighboring cells, hormones, and extracellular matrix

28. Apoptosis Abnormal inhibition of Apoptosis: cancer Abnormal high rate of apoptosis: degenerative disease (e.g. Osteoporosis)

29. Aging Physiologic manifestations: Gradual detrioration in the function of virtually all tissues and organs systems Deterioration of the homeostatic control systems to respond to environmental stresses Decrease in the number of cells in the body Decreased cell division Increase cell death Malfunction of remaining cells Immediate cause: Interference in the function of the cells macromolecules (e.g. DNA)

30. Aging Decreased cell division Built in limit to the number of times a cell divides DNA loses a portion of its terminal segment (telomere) each time it replicates Genetic and environmental factors Progressive damage Variability of lifespan: 1/3- genes 2/3- differing environments

31. Aging Genes Probably those that code for proteins that regulate the processes of cellular and macromolecular maintenance and repair Werner’s syndrome: premature aging due to a mutation of a single gene that is critical for DNA replication or repair Difficulty in determining if changes in the body are due to aging or disease Can the aging process be inhibited or slowed down? Exerise Balanced diet: reduces formation of free radicals

32. Balance in the Homeostasis of Chemicals Balance diagram for a chemical substance

33. Balance in the Homeostasis of Chemicals Exception to scheme: mineral electrolytes Can’t be synthesized Do not normally enter thru lungs Can’t be removed by metabolism e.g. Na+ Generalizations of the balance concept: During any period of time, total-body balance depends upon the relative rates of net gain and net loss to the body 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

34. Balance in the Homeostasis of Chemicals 3 states of total-body balance Negative balance: Loss exceeds gain amount of substance in the body is decreasing Positive balance: gain exceeds loss, amount in body increasing Stable balance: gain = loss A stable balance can be upset by alteration of the amount being gained or lost in a single pathway in the schema

35. Section B: Mechanisms by which chemical messengers control cells Homeostatic Mechanisms and Cellular Communication

36. Receptors Chemical Proteins: ligands Receptors: target cell proteins Binding site Glycoproteins located Plasma membrane More common Transmembrane CHONs Has segments extracellular, within the membrane, and intracellular Where lipid-insoluble messengers bind Intracellular Mainly in the nucleus Where lipid soluble chemical messengers bind

37. Receptors Specificity: A very important characteristic of Intercellular communication Cells differ in types of receptors they contain Frequently, just one cell type possesses the receptor required for the combination with a given chemical messenger “superfamilies” : group of receptors closely related structurally for a group of messengers

38. Receptors Different cell types may possess the same receptors for a particular messenger, but responses to the same messenger may differ Receptor functions as a molecular switch that switches on when a messenger binds to it e.g. Norephinephrine Smooth muscle of blood vessel contract Pancreas  decrease insulin secretion A single cell may contain several different receptor types for a single messenger Response different from one receptor to another in the same cell e.g. 2 epinephrine receptor sites in smooth muscle cells of BV (contraction vs dilation) 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

39. Receptors A single cell contains many different receptors for different chemical messengers Saturation: response increases as extracellular concentration of the messener increases Upper limit to responsiveness due to finite number of receptors available that become saturated at a point Competition: Ability of different messenger molecules that are very similar in structure to compete with each other for a receptor Antagonist: drugs that bind on the receptors without activatng them prevent messengers from binding and triggering a response e..g. B-blockers

40. Receptors Agonist: Drugs that bind on a particular receptor and trigger the cell’s response as if a true chemical messenger had combined with the receptor e.g. Ephidrine  epinephrine receptors Down-regulation: High ECF messenger concentration  target cell receptors decrease Reduces target cells’ responsiveness to frequent or intense stimulation by a messenger Local negative feedback mechanism e.g. Insulin  glucose uptake  decrease insulin receptors Up-regulation: Cells exposed to a prolongd period of very low concentrations of a messenger maydevelop many more receptors for the messenger e.g. Denervated muscls contract when injected with small amounts of neurotransmitter

41. Receptors Down-regulation Binding of messengers to receptors endocytosis  degradation of receptors Up-regulation Stores of receptors in IC vessicles insertion via exocytosis Gene that code for receptors Alteration of expression during down/up-regulation Receptors may decrease or increase due to a disease process Myasthenia gavis: aceylcholine receptors in muscles are destroyed mscle weakness/destruction

42. Signal Transduction Pathways The sequences of events between receptor activation and the cell’s response Signal: Receptor activation Transduction: Process in which stimulus is transformed into a response Lipid-soluble messengers: Receptors inside the cell Lipid-insoluble messengers Receptors in the plasma membrane of cell

43. Signal Transduction pathways Receptor activation: Initial step leading to the cell’s ultimate responses to the messenger Causes a change in the conformation of the receptor Common denominator: all directly due to alterations of a particular cell protein Changes may be in the form of: Permeability, transport properties, or electrical state of the plasma membrane The cell’s metabolism The cell’s secretory activity The cell’s rate of proliferation and differentiation Cell’s contractile activity

44. Signal Transduction Pathways Pathways initiated by intracellular pathways Lipid soluble messengers mostly hormones Closely related structurally Receptors Steroid hormone receptor superfamily Intracellular, mostly in the nucleus Inactive when not bound to messenger Activation altered rates og gene transcription Transcription Factor Receptor + Hormone Regulatory protein that directly influences gene transcription Response element: specific sequence near a gene in DNA where the receptor binds Increases the rate of the gene’s transcription into mRNA mRNA direct synthesis of CHON encoded by the gene One gene may be subject to control by a single receptor In some cases, transcription of the gene/s is decreased by the activated receptor

45. Signal Transduction Pathway

46. Signal Transduction Pathway Pathways initiated by Plasma membrane receptors First messengers Intercellular chemical messenger Hormones, neurotransmitters, paracrine agents Second messengers Non protein substance/enzymatically generated  cytoplasmtransmit signals Protein kinase Any enzyme that phosphorylates other CHONs by transfering them a PO4 group from ATP Changes the activity and sonformation of the CHON May involve may CHON kinase

47. Signal Transduction Pathway Receptors that Function as ion channels Receptor constitute an ion channel Activation  opening of channels  diffusion of specific channels change in membrane potential cell’s response Ca++ channel  increase cytostolic Ca++ conc.  essential for signal transduction pathways

48. Signal Transduction Pathways Receptors that function as enzymes With intrinsic enzyme activity Almost all are protein-kinases, mostly tyrosine-kinases 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 Guanylyl cyclase receptor: Catalyzes formation of cGMP (2nd messenger)  activation of cGMP-dependent protein kinase  phosphorylation of a CHON  cell’s response

49. Signal Transduction Pathways Receptors that interact with Cytoplasmic JAK Kinases Receptor with intrinsic enzmatic activity Enzymatic activity on receptor’s tyrosine kinase and on separate cytoplasmic kinases (JAK kinases)bound to the receptor Receptor and JAK kinase: function as a unit Messenger  receptor  activation of JAK kinase  phoshorylation of CHONs  transcription factors  synthesis of new CHONs that mediate cell’s response

50. Signal Transduction Pathways Receptors that interact with G proteins Largest group of receptors G-proteins on the cytoplasm is bound to the receptors Messenger  receptor conformational change  1 of 3 subunits of G-proteins link with plasma membrane effector proteins  sequence of events  cell’s response G-proteins: serve as a switch to couple a receptor with an ion channel or an enzyme in plasma membrane

51. Signal Transduction Pathway Effector Protein Enzymes: Adenylyl cyclase and Cyclic AMP Phospholipase C, diacylglycerol, and Inositol Triphosphate

52. Signal Transduction Pathway Adenylyl cyclase and cyclic AMP Messenger  receptor  activation of G protein  activation of Adenylyl Cyclase  conversion of ATP  cAMP (2nd messenger) sequence of events  cell’s response Phosphodiesterase: enzyme that breaks down cAMP to non cyclic AMP, thus termination of its action cAMP  activation cAMP dependent protein kinase (Protein-kinase A)  phosphorylation of proteins  cell response Amplification: 1 active adenylyl cyclase  catalyzation of > 100 cAMP molecules cAMP dependent protein kinase can phosphorylate large number of different proteins  exert multiple actions on a cell cAMP dependent protein kinase may inhibit other enzymes

53. Signal Transduction Pathway

54. Signal Transduction Pathways

55. Signal Transduction Pathways

56. SignalTransduction Pathways Phospholipase C, Diacylglycerol, and Inositol Triphosphate Gq phospholipase C  breakdown of PIP2  DAG and IP3  different sequence cascade  cell response DAG  activates protein kinase C  phosphorylation of many proteins  cell response 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

57. Signal Transduction Pathways

58. Signal Transduction Pathways Control of ions by G Proteins Direct G-protein gating (fig 7-13d) G-protein interacts directly with ion channels in PM All events occur in the plasma membrane No 2nd messengers involved Indirect G-protein gating (fig 7-17) Utilizes a 2nd messenger

59. Signal Transduction Pathways Ca++ ion as a 2nd messenger Ca++ is maintained extremely low in cytosol Large electrochemical gradient favoring diffusion of Ca++ via channels in both PM and ER Stimulus: change cytostolic Ca++ levels Active transport systems Ion channels Ca++ channels openingChemical stimuliElectrical gradient Ca++ (2nd messenger)  bind channels in ER opening of channels  release of Ca++ from ER ( calcium-induced calcium release) 2nd messenger IP3 Ca++

60. Signal Transduction Pathways Ca++ ions as 2nd messenger Ca++ can bind with various CHONs Ca++ binding alters CHON conformation and activates their function Calmodulin + Ca++  change in shape activation/inhibition of protein kinases Calmodulin –dependent protein kinase activation/inibition  phosphorylation  activation/inibition of CHONs  cell response

61. Signal Transuction Pathways

62. Signal Transduction Pathways Receptors and Gene Transcription Plasma membrane receptors: transduction pathways activate Intracellular transcription factors using 2nd messengers Primary Response Genes: Genes with transcription factors activated by first messenger Proteins encoded by PRGs may itself be a transcription factor for another gene

63. Signal Transduction Pathways Cessation of activity in signal transduction Key event: cessation of receptor activation Decrease in the concentration of the first messenger molecules in the region of the receptor Metabolism by enzymes in the vicinity Uptake by adjacent cells Diffusion away Chemical alteration of the receptor (usually by phosphorylation) Lower affinity for the 1st messenger Release of the messenger Removal of plasma membrane receptor and its endocytosis

64. Signal Transduction Pathways