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Human physiology part 3 homeostatic mechanisms and cellular communication chapter 7 vander l.jpg

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

John Paul L. Oliveros, MD


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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 “


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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


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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


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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


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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


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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


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Components of homeostatic control systems

  • Reflexes

  • Local homeostatic responses


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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


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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



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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


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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


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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


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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


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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


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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


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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


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Processes Related to Homeostasis

  • Acclimatization

  • Biological rhythms

  • Regulated Cell Death: Apoptosis

  • Aging

  • Balance in the homeostasis of chemicals


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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


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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.


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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


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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


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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)


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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


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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


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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


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Apoptosis

  • Abnormal inhibition of Apoptosis:

    • cancer

  • Abnormal high rate of apoptosis:

    • degenerative disease (e.g. Osteoporosis)


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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)


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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


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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


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Balance in the Homeostasis of Chemicals

  • Balance diagram for a chemical substance


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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


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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


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Homeostatic Mechanisms and Cellular Communication

Section B: Mechanisms by which chemical messengers control cells


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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


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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


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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


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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


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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


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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


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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


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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


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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



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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


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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


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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


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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


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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


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Signal Transduction Pathway

  • Effector Protein Enzymes:

    • Adenylyl cyclase and Cyclic AMP

    • Phospholipase C, diacylglycerol, and Inositol Triphosphate


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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





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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



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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


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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++


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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



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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


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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



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