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    Second Messenger Action, cAMP & CGMP

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    Sandra
    1. Cyclic GMP (cGMP) and cyclic AMP (cAMP) are important intracellular second messengers that relay signals from receptors on the cell surface to target molecules in the cytosol and nucleus. 2. cGMP signals are involved in processes like smooth muscle relaxation and phototransduction in the eye. It signals through activation of protein kinase G. 3. cAMP signals are involved in processes like glycogenolysis and regulates enzymes/gene expression through protein kinase A. 4. Both are synthesized by cyclase enzymes, signal through kinase pathways, and degraded by phosphodiesterases to terminate the signal.

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    Second Messenger Action, cAMP & CGMP

    Uploaded by

    Sandra
    41 views27 pages
    1. Cyclic GMP (cGMP) and cyclic AMP (cAMP) are important intracellular second messengers that relay signals from receptors on the cell surface to target molecules in the cytosol and nucleus. 2. cGMP signals are involved in processes like smooth muscle relaxation and phototransduction in the eye. It signals through activation of protein kinase G. 3. cAMP signals are involved in processes like glycogenolysis and regulates enzymes/gene expression through protein kinase A. 4. Both are synthesized by cyclase enzymes, signal through kinase pathways, and degraded by phosphodiesterases to terminate the signal.

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    second messenger action, cAMP & cGMP (1)

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    1. Cyclic GMP (cGMP) and cyclic AMP (cAMP) are important intracellular second messengers that relay signals from receptors on the cell surface to target molecules in the cytosol and nucleus. 2. cGMP signals are involved in processes like smooth muscle relaxation and phototransduction in the eye. It signals through activation of protein kinase G. 3. cAMP signals are involved in processes like glycogenolysis and regulates enzymes/gene expression through protein kinase A. 4. Both are synthesized by cyclase enzymes, signal through kinase pathways, and degraded by phosphodiesterases to terminate the signal.

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    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    41 views27 pages

    Second Messenger Action, cAMP & CGMP

    Uploaded by

    Sandra
    1. Cyclic GMP (cGMP) and cyclic AMP (cAMP) are important intracellular second messengers that relay signals from receptors on the cell surface to target molecules in the cytosol and nucleus. 2. cGMP signals are involved in processes like smooth muscle relaxation and phototransduction in the eye. It signals through activation of protein kinase G. 3. cAMP signals are involved in processes like glycogenolysis and regulates enzymes/gene expression through protein kinase A. 4. Both are synthesized by cyclase enzymes, signal through kinase pathways, and degraded by phosphodiesterases to terminate the signal.

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    of 27

    GENERAL SCHEME OF SECOND MESSENGER ACTION

    NUCLEOTIDES- cAMP & cGMP


    GENERAL FEATURES OF SECOND MESSENGERS
    Are intracellular messengers that have some properties in common:

    1. They can be synthesized/released and broken down again in specific reactions


    by enzymes or ion channels. The hormone must appropriately effect the
    enzymes of synthesis and/or degradation of the mediator

    e.g. Adenylate cyclase catalyses synthesis of cAMP, while cyclic nucleotide


    phosphodiesterase (PDE) inactivates cAMP

    2. An appropriate temporal relationship must exist among the hormone, mediator


    and hormonal effect.
    Some (like Ca2+) can be stored in special organelles and quickly released when
    needed.

    3. The hormone must induce elevated levels of the mediator. Their production and
    destruction can be localized, enabling the cell to limit space and time of signal
    activity.

    4. The mediator or its analog must mimic the action of the hormone, which cannot
    enter the cell.

    5. If drugs are available to modulate the endogenous level of the mediator, they
    should also mimic or inhibit, as appropriate the effects of the hormone.
    SECOND MESSENGERS
    • Relay signals received at receptors on the
    cell surface to target molecules in the
    cytosol or nucleus.

    • In addition they serve to greatly amplify the


    strength of the signal.

    • Binding of a ligand to a single receptor at


    the cell surface may end up causing
    massive changes in the biochemical
    activities within the cell.
    cAMP

    The cAMP signal transduction contains 5 main characters:

    • stimulative hormone receptor (Rs) or inhibitory hormone receptor (Ri)


    • Stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi)
    • Adenylyl cyclase
    • Protein Kinase A (PKA)
    • cAMP phosphodiesterase.

    • Stimulative regulative G-protein is a G-protein linked to stimulative hormone


    receptor (Rs)

    • and its α subunit upon activation could stimulate the activity of an enzyme or
    other intracellular metabolism.

    • On the contrary, inhibitory regulative G-protein is linked to an inhibitory


    hormone receptor

    • and its α subunit upon activation could inhibit the activity of an enzyme or
    other intracellular metabolism.
    cAMP
    • The Adenylyl cyclase is a transmembrane
    glycoprotein that catalyzes ATP to form
    cAMP with the help of cofactor Mg2+ or
    Mn2+.
    • Cyclic AMP (cAMP)- is synthesized from
    ATP by the action of the enzyme adenylyl
    cyclase.

    • The cAMP produced is a second messenger


    in cellular metabolism and is an allosteric
    activator to Protein kinase A.
    cAMP
    • Protein kinase A is an important enzyme in cell
    metabolism due to its ability to regulate cell
    metabolism:

    • by phosphorylating specific committed enzymes


    in the metabolic pathway

    • and it can also regulate specific gene expression

    • cellular secretion

    • membrane permeability.
    Protein kinase A
    • The protein enzyme contains two catalytic subunits and
    two regulatory subunits.

    • When there is no cAMP，the complex is inactive.

    • When cAMP binds to the regulatory subunits, their


    conformation is altered,

    • causing the dissociation of the regulatory subunits, which


    activates protein kinase A and allows further biological
    effects.

    • cAMP phosphodiesterase is an enzyme that can degrade


    cAMP to 5'-AMP, which will terminate the signal.
    cAMP
    • HORMONES THAT USE cAMP:
    • Epinephrine and norepinephrine
    • Glucagon
    • Luteinizing hormone
    • follicle stimulating hormone,
    • thyroid-stimulating hormone
    • Calcitonin
    • parathyroid hormone
    • antidiuretic hormone
    Protein kinase A

    • Binding of the hormone to its receptor activates a G


    protein which, in turn, activates adenylyl cyclase.

    • The resulting rise in cAMP turns on the appropriate


    response in the cell by either/ or:

    1. changing the molecular activities in the cytosol, often


    using Protein Kinase A (PKA) — a cAMP-dependent protein
    kinase that phosphorylates target proteins

    2. turning on a new pattern of gene transcription.


    Protein kinase A
    • The cyclic AMP then goes on to activate specific
    proteins.

    • Some ion channels, for example, are gated by


    cyclic AMP.

    • But an especially important protein activated by


    cyclic AMP is protein kinase A

    • which goes on to phosphorylate certain cellular


    proteins.

    • The scheme below shows how cyclic AMP


    activates protein kinase A.
    EXAMPLE : MODE OF ACTION OF PEPTIDE HORMONE

    • Glucagon binds its receptor in the plasma membrane of target cells


    e.g. hepatocytes.

    • Bound receptor interacts with and, through a set of G proteins, turns


    on adenylate cyclase, which is also an integral membrane protein.

    • Activated adenylate cyclase begins to convert ATP to cyclic AMP,


    resulting in an elevated intracellular concentration of cAMP.

    • High levels of cAMP in the cytosol make it probable that protein kinase
    A will be bound by cAMP and therefore catalytically active.

    • Active protein kinase A "runs around the cell" adding phosphates to


    other enzymes, thereby changing their conformation and modulating
    their catalytic activity - the cell has been changed.

    • Levels of cAMP decrease due to destruction by


    cAMP-phosphodiesterase and the inactivation of adenylate cyclase.
    cAMP
    • HORMONES THAT USE PROTEIN KINASE:
    • Insulin
    • growth hormone
    • Prolactin
    • Oxytocin
    • Erythropoietin
    • several growth factors
    cGMP
    Cyclic GMP is synthesized from the nucleotide GTP using the
    enzyme guanylyl cyclase.

    • Cyclic GMP serves as the second messenger for

    • atrial natriuretic peptide (ANP)

    • nitric oxide (NO)

    • response of the rods of the retina to light.

    • Some of the effects of cGMP are mediated through Protein


    Kinase G (PKG)

    • a cGMP-dependent protein kinase that phosphorylates


    target proteins in the cell.
    Effects of cGMP
    • cGMP is a common regulator of ion channel conductance,
    glycogenolysis, and cellular apoptosis.

    • It also relaxes smooth muscle tissues. In blood vessels, relaxation of


    vascular smooth muscles lead to vasodilation and increased blood
    flow.

    • cGMP is a secondary messenger in phototransduction in the eye. In


    the photoreceptors of the mammalian eye, the presence of light
    activates phosphodiesterase, which degrades cGMP.

    • The calcium ion channels in photoreceptors are cGMP-gated, so


    degradation of cGMP causes calcium channels to close,

    • which leads to the hyperpolarization of the photoreceptor's plasma


    membrane and ultimately to visual information being sent to the brain
    Protein kinase G
    • cGMP is involved in the regulation of some
    protein-dependent kinases.

    • For example, PKG (protein kinase G) is a dimer consisting


    of one catalytic and one regulatory unit,

    • with the regulatory units blocking the active sites of the


    catalytic units.

    • cGMP binds to sites on the regulatory units of PKG and


    activates the catalytic units, enabling them to
    phosphorylate their substrates.

    • Unlike with the activation of PKA, the PKG is activated but


    the catalytic and regulatory units do not disassociate.
    Degradation of cGMP
    • Numerous cyclic nucleotide
    phosphodiesterases (PDE) can degrade
    cGMP by hydrolyzing cGMP into 5'-GMP.

    • PDE 5, -6 and -9 are cGMP-specific while


    PDE1, -2, -3, -10 and -11 can hydrolyse both
    cAMP and cGMP.

    • Phosphodiesterase inhibitors prevent the


    degradation of cGMP, thereby enhancing
    and/or prolonging its effects.

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