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    Day 22 Signaling 1: General Concepts and cAMP Pathway: - You Should Be Able To Explain

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    shouq huusain
    Here is my attempt at answering Problem 15-51: In the absence of adrenaline: - A nonhydrolyzable GTP analog would lock the G protein in its active, GTP-bound state even without receptor stimulation by adrenaline. This would constitutively activate the downstream signaling pathway, leading to continual glycogen breakdown even without adrenaline present. After a brief exposure to adrenaline: - Adrenaline would further activate the G protein and enhance the signaling pathway. However, the effect would not be transient since the G protein could not hydrolyze GTP to the inactive GDP state to turn off the signal. This would lead to prolonged glycogen breakdown even after adrenaline was removed. Exposure to for

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    Day 22 Signaling 1: General Concepts and cAMP Pathway: - You Should Be Able To Explain

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    shouq huusain
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    Here is my attempt at answering Problem 15-51: In the absence of adrenaline: - A nonhydrolyzable GTP analog would lock the G protein in its active, GTP-bound state even without receptor stimulation by adrenaline. This would constitutively activate the downstream signaling pathway, leading to continual glycogen breakdown even without adrenaline present. After a brief exposure to adrenaline: - Adrenaline would further activate the G protein and enhance the signaling pathway. However, the effect would not be transient since the G protein could not hydrolyze GTP to the inactive GDP state to turn off the signal. This would lead to prolonged glycogen breakdown even after adrenaline was removed. Exposure to for

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    Here is my attempt at answering Problem 15-51: In the absence of adrenaline: - A nonhydrolyzable GTP analog would lock the G protein in its active, GTP-bound state even without receptor stimulation by adrenaline. This would constitutively activate the downstream signaling pathway, leading to continual glycogen breakdown even without adrenaline present. After a brief exposure to adrenaline: - Adrenaline would further activate the G protein and enhance the signaling pathway. However, the effect would not be transient since the G protein could not hydrolyze GTP to the inactive GDP state to turn off the signal. This would lead to prolonged glycogen breakdown even after adrenaline was removed. Exposure to for

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    31 views20 pages

    Day 22 Signaling 1: General Concepts and cAMP Pathway: - You Should Be Able To Explain

    Uploaded by

    shouq huusain
    Here is my attempt at answering Problem 15-51: In the absence of adrenaline: - A nonhydrolyzable GTP analog would lock the G protein in its active, GTP-bound state even without receptor stimulation by adrenaline. This would constitutively activate the downstream signaling pathway, leading to continual glycogen breakdown even without adrenaline present. After a brief exposure to adrenaline: - Adrenaline would further activate the G protein and enhance the signaling pathway. However, the effect would not be transient since the G protein could not hydrolyze GTP to the inactive GDP state to turn off the signal. This would lead to prolonged glycogen breakdown even after adrenaline was removed. Exposure to for

    Copyright:

    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
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    Day 22 Signaling 1: General Concepts and cAMP pathway

    • Wednesday, Oct. 7: Chemical signaling 1, • You should be able to explain:


    Ch. 15 • Some general concepts of chemical
    signaling.
    – Final chance on Spike homework (first
    • How G protein-coupled receptors work,
    submission OR revision) due 1 PM including inhibitors for functional studies.
    • Friday, Oct. 9: Chemical signaling 2, Ch. 15 • The complete cAMP pathway, using the
    fight or flight response as an example.
    • Monday, Oct. 12: Signaling 3, Ch. 15
    – Quiz on Week 8 due 1 PM

    Signaling 1: General Concepts and cAMP


    Pathway
    A. Signaling concepts
    B. G Protein-Coupled Receptors
    C. cAMP Pathway
    A. General Concepts of Cell
    Signaling

    A General Signal Transduction Pathway:


    Forms of Intercellular Signaling

    Aka cytokines, growth/differentiation factors, paracrine factors


    Multiple Inputs For Cellular Response;
    Multiple Responses to Same Signal

    ^ Different responses in different cell types


    (unrelated)

    Can also have coordinated response, e.g. ”fight or


    flight” response to epinephrine (adrenaline)
    Classes of Cell-Surface Receptors
    Aka ligand-gated channels, e.g. acetylcholine receptor

    e.g. adrenaline response

    e.g. many growth/differentiation factors


    Chemical Signals (Primary messengers)
    • Are diverse: can be amino
    acids/derivatives, peptides, proteins,
    fatty acids, lipids,
    nucleotides/derivatives.

    • Water soluble ligands bind to plasma e.g. steroid


    membrane receptors. hormone

    • Lipid soluble ligands diffuse across the


    MB, bind to intracellular receptors.
    Cellular Responses Can Be Fast or Slow

    Regulated protein function New gene expression


    Receptor desensitization (adaptation)

    • Caused be prolonged exposure to signaling ligand.


    • Allows cell to adapt to changes in concentration of ligand.
    7-pass TM protein

    Heterotrimeric G protein: GS

    B. G-protein-Coupled Receptors:
    Example: β-adrenergic No ligand: GDP bound to G protein
    receptor for adrenaline
    G Protein Activation Cycle and Types

    RSGS and RIGI, from Lodish et al. 2000. Molecular Cell Biology, 4th Ed.
    G protein Targets: Enzymes
    1. L binds RS linked to GS (+) adenylyl cyclase  ATP to cAMP.
    – Disease GOF: Cholera toxin (+) GS so can’t turn off A.C. which (+) CFTR Cl- channel in intestine, results in
    oversecretion of ions and water > dehydration.
    – LOF: Beta-blocker drugs prevent binding of epi to receptor, lowering blood pressure and increasing
    vasodilation.
    2. L binds RI linked to GI (-) adenylyl cyclase  no conversion of ATP to cAMP.
    – Disease GOF: Pertussis toxin (-) GI so can’t turn off A.C., results in fluid accumulation in lungs.
    3. Odor  olfactory receptor linked to Golf (+) adenylyl cyclase  cAMP-gated cation
    channels  action potential.
    4. L binds R linked to Gq (+) phospholipase C  PIP2 to IP3 and DAG and cause Ca2+ release.
    5. Light  rhodopsin linked to GT (+) cGMP phosphodiesterase  cGMP to GMP  action
    potential.
    Second Messengers and G Protein Poisons
    • G proteins activate or inhibit enzymes that
    produce or remove second messengers, which
    relay signal from membrane to intracellular
    locations
    – cAMP (cyclic AMP)
    – cGMP (cyclic GMP)
    – IP3 (inositol trisphosphate), DAG (diacylglycerol)
    – Ca2+
    • Poisons:
    – Nonhydrolyzable GTP analogs: lock on > Causes G protein to
    – Cholera toxin (+) GS so can’t turn off A.C. which (+) be locked “ON”
    CFTR Cl- channel, results in over-secretion of ions
    and water > dehydration
    – Pertussis toxin (-) GI so can’t turn off A.C., results in
    fluid accumulation in lungs
    • These two toxins used to distinguish if cellular process
    requires GS or GI
    “Fight or flight”

    Also: Nose Odor, phereomone Smell


    C. cAMP Example: “Fight or flight” response
    YOU MUST LEARN THIS PATHWAY – Practice Drawing It

    • Signal: Epinephrine (adrenaline)


    • Receptor:  adrenergic receptors (RS) (-) beta blockers

    • Transducer: GS
    • Amplifier: adenylyl cyclase
    • Second Messenger: ATP → cAMP
    • 2nd Messenger Target: Protein Kinase A
    • Downstream Targets: Protein kinase cascade
    • Cellular Response: Flight or fight responses:
    ↑heart rate, force; glycogen, fat breakdown

    *What turns off the signal at each step?


    Adenylyl cyclase produces cAMP,
    cAMP PDE degrades cAMP

    Mint family herb Coleus forskohlii


    forskolin (+)

    theophylline, caffeine (-)


    Do these drugs cause a
    loss or gain of function?
    Does this demonstrate necessity
    or sufficiency?
    Caffeine effects on the body
    • Caffeine’s most notable pharmacological effect is as a central nervous
    system stimulant, increasing alertness and producing agitation. It also
    relaxes smooth muscle, stimulates cardiac muscle, stimulates diuresis,
    and appears to be useful in the treatment of some types of headache.
    Several cellular actions of caffeine have been observed, but it is not
    entirely clear how each contributes to its pharmacological profile.
    Among the most important are inhibition of cyclic nucleotide
    phosphodiesterases, antagonism of adenosine receptors, and
    modulation of intracellular calcium handling. [PubChem]

    http://www.drugbank.ca/drugs/DB00201#pharmacology
    cAMP effects

    cAMP

    Protein kinase A

    ATP + Pro  ADP + Pr*-PO32-
    (Phosphorylation
    of target proteins)

    Cellular response
    (e.g. fight or flight)
    Protein Kinase A (PKA)

    • PKA composed of 2
    regulatory, 2 catalytic
    subunits
    • cAMP binds regulatory
    subunits
    • Subunits break apart and
    catalytic subunits
    phosphorylate target
    proteins.
    PKA can mediate cytosolic and/or nuclear effects

    Rapid effects in cytosol

    New gene expression (slower); e.g. neurons in brain


    synthesizing new proteins during learning
    Activity: Problem 15-51
    When adrenaline (epinephrine) binds to adrenergic receptors on
    the surface of a muscle cell, it activates a G protein, initiating a
    signaling pathway that results in breakdown of muscle glycogen.
    How would you expect glycogen breakdown to be affected if
    muscle cells were injected with a nonhydrolyzable analog of GTP,
    which can’t be converted to GDP? Consider what would happen
    in the absence of adrenaline and after a brief exposure to it.
    Would exposure to to forskolin have an identical effect or not?

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