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human physiology part 3 homeostatic mechanisms and cellular communication chapter 7 vander

Human physiology part 3Homeostatic Mechanisms and cellular communication(Chapter 7 vander)

John Paul L. Oliveros, MD

general characteristics
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 “
general characteristics3
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
general characteristics4
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
general characteristics5
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
general characteristics6
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
general characteristics7
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
components of homeostatic control systems
Components of homeostatic control systems
  • Reflexes
  • Local homeostatic responses
  • 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
reflex arc
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
  • 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
local homeostatic response
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
intercellular chemical messengers
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
intercellular chemical messengers15
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
intercellular chemical messengers16
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
intercellular chemical messengers17
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
intercellular chemical messengers18
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
processes related to homeostasis
Processes Related to Homeostasis
  • Acclimatization
  • Biological rhythms
  • Regulated Cell Death: Apoptosis
  • Aging
  • Balance in the homeostasis of chemicals
  • 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
biological rhythms
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.
biological rhythms22
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
biological rhythms23
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
biological rhythms24
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)
biological rhythms25
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
  • 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
  • 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
  • Abnormal inhibition of Apoptosis:
    • cancer
  • Abnormal high rate of apoptosis:
    • degenerative disease (e.g. Osteoporosis)
  • 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)
  • 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
  • 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
balance in the homeostasis of chemicals
Balance in the Homeostasis of Chemicals
  • Balance diagram for a chemical substance
balance in the homeostasis of chemicals33
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
balance in the homeostasis of chemicals34
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
homeostatic mechanisms and cellular communication
Homeostatic Mechanisms and Cellular Communication

Section B: Mechanisms by which chemical messengers control cells

  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
signal transduction pathways
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
signal transduction pathways43
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
signal transduction pathways44
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
signal transduction pathway46
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
signal transduction pathway47
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
signal transduction pathways48
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
signal transduction pathways49
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
signal transduction pathways50
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
signal transduction pathway51
Signal Transduction Pathway
  • Effector Protein Enzymes:
    • Adenylyl cyclase and Cyclic AMP
    • Phospholipase C, diacylglycerol, and Inositol Triphosphate
signal transduction pathway52
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
signal transduction pathways56
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
signal transduction pathways58
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
signal transduction pathways59
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++
signal transduction pathways60
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
signal transduction pathways62
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
signal transduction pathways63
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