Human physiology part 3

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  • 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