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

•    G_s, G_i, G_q and G₁₂

–  Each differ by alpha subunit (α_s and α_i 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:

–  α_s activates Adenylyl cyclase, Ca²⁺, Na⁺, Cl^- Channels

–  α_i activates K⁺ channels

–  α_q activates Phospholipase C

–  α_t 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

–  α_s - GTP activates AC and increase the level of cAMP

–  α_i - 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