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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