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Mechanism of Hormone action

 

Mechanism of Hormone action

    Many hormone act as inducer or repressor of genetically controlled synthesis of key enzyme systems

    The mechanism of hormone actions is well known today but the exact site of action of any hormone is still not well understood

    Following mechanisms of action have been proposed

  Interaction with nuclear chromatin

  Membrane receptor interactions

  Enzyme synthesis at ribosomal level Direct action of enzyme system

i) Mechanism of action of steroidal hormone:

    Interaction with nuclear chromatin (nuclear action)

    Steroid hormones mostly act by changing transcription rate of specific genes

Act on specific, soluble, oligomeric receptor protein

    Mobile receptors

  Conformational changes and alteration in the surface charges of protein receptors

  Receptor –steroid complex moves to chromatin and binds to hormone responsive element (HME) of DNA

  Changes in the concentration of intracellular mRNA alters the synthesis of proteins

Structure, enzymatic, carrier or receptor proteins

 

ii) Mechanism of action of Protein hormones:

    Protein hormones being water soluble do not require any carrier protein

  Binds to the cell surface receptors

  act through second messengers in a cell

    Second messenger are produced as intracellular signals to carryout cell responses

         cAMP, cGMP, Ca2+ ions, phosphatidylinositides etc.

    G-Protein coupled receptors: (GPCR)

    Also called Serpentine receptors, 7TM receptors

    Many protein hormones bind to the receptor that are linked  to effectors through a guanine binding protein (G-protein) intermediary

    Structure of serpentine receptor:

  Seven α-helical hydrophobic plasma membrane – spanning domains Often demonstrated as seven   interconnected cylinders extending   through lipid bilayer

    G-proteins are heterotrimeric proteins consisting of α, β and γ subunits

  There are 21α, 5β and 8γ subunit genes

  Their combination provide a large number of possible αβγ complexes

  Depending on protein sequences conservation four major classes of G-proteins have been identified

    Gs, Gi, Gq and G12

  Each differ by alpha subunit (αs and αi etc.)

    The α-subunits bind guanine nucleotide

  The β and γ subunits are mostly associated as dimer

    The binding of hormone to receptor results in the receptor mediated activation of G-protein

    The ability of a hormone to stimulate or inhibit effector depends upon the type of G-protein

 

    GTP attached to G-proteins results in the dissociation of α-subunits from βγ

  α-Subunit attached with GTP is active

  Hydrolysis of GTP to GDP deactivates the α-Subunit

    The α-subunits binds and activates the effector depending upon α-Subunit type:

  αs activates Adenylyl cyclase, Ca2+, Na+, Cl- Channels

  αi activates K+ channels

  αq activates Phospholipase C

  αt activates cGMP Phophodiesterase

    The βγ subunits can also have direct action on effector

    G-protein activates enzyme to produce second messengers that phosphorylate or dephosphorylate proteins that in turn control gene expression

    Adenylyl Cyclase (AC):

    Cyclic AMP is a nucleotide derived from ATP by the action of enzyme adenylyl cyclase (AC)

  First intracellular second messenger signal identified in mammalian cells

    Its level may increase or decrease by hormonal action depending upon tissue and receptor types

  αs - GTP activates AC and increase the level of cAMP

  αi - GTP inhibits AC and decrease cAMP

    cAMP activates some protein kinase enzymes allosterically and influences gene expression

  E.g. the activation of protein kinase in glycogen metabolism

    Phosphodiesterases deactivate cAMP by hydrolysis


    Phopholipase C:

    Activated G-Protein coupled receptor (GPCR) can also activates phopholipase C

    Phospholipase C acts on Phosphotidylinositol4,5- bisphosphate and produce two second messengers

  Inositoltriphosphate (IP3)

    Increase the Ca2+ into the cytosol from within cell

    Activates Ca2+ -Calmodulin dependent kinases & other enzymes

  Diacyl glycerol (DAG)

    Activates Protein kinase C

  These results in the increased phosphorylation of specific enzyme proteins and modulate their activities

 

    Protein kinase cascade:

    Specialized enzyme(s) activated by second messengers

  May act as single enzyme or multi-enzyme system

    Protein kinase A (PKA)

    Protein kinase C (PKC)

    Ca2+ – Calmudolin kinase (CaM-Kinase) etc

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