Second Messengers: Bhaskar Ganguly PH.D., M.V.SC., B.V.Sc. & A.H
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Bhaskar GangulySecond Messengers: Bhaskar Ganguly PH.D., M.V.SC., B.V.Sc. & A.H
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Bhaskar GangulySecond
Messengers
Bhaskar Ganguly
Ph.D., M.V.Sc., B.V.Sc. & A.H.
Second messengers are intracellular
chemical signals, the concentration of
which
is
regulated
by
hormones,
neurotransmitters, and other extracellular
signals. They arise from easily available
substrates and only have a short half-life.
The most important second messengers
are
cAMP,
cGMP,
Ca2+,
inositol
triphosphate (IP3), diacylglycerol (DAG),
and nitrogen monoxide (NO).
Cyclic AMP (cAMP)
METABOLISM:
Adenosine 3,5-cyclic monophosphate
Synthesized by membrane-bound adenylate cyclases
that cyclize ATP to cAMP by cleaving diphosphate (PPi)
Degradation of cAMP to AMP is catalyzed by
phosphodiesterases
Phosphodiesterases
are
inhibited
by
methylxanthines such as caffeine; insulin activates
the esterase and thereby reduces the cAMP level
Adenylate cyclase activity is regulated by G
proteins (Gs and Gi), which in turn are controlled by
extracellular signals via 7-helix receptors
Ca2+-Calmodulin also activates specific adenylate
cyclases
Cyclic AMP (cAMP)
ACTION:
An allosteric effector of protein kinase A (PK-A)
In the inactive state, PK-A is a hetero-tetramer
(C2R2)
Catalytic
subunits (C) are blocked by
regulatory units (R; autoinhibition)
When cAMP binds to the regulatory units, the C
units separate from the R units and become
enzymatically active
Active PK-A phosphorylates serine and threonine
residues of more than 100 different proteins,
enzymes, and transcription factors
cGMP
Guanosine 3,5-cyclic monophosphate
Synthesized by guanylate cyclases; degraded to
GMP by cGMP phosphodiesterase
Key cGMP mediated processes include vision and
vasodilation
Role of cGMP in vision
Role of cGMP in vasodilation
Inositol 1,4,5-trisphosphate (IP3) &
Diacylglycerol (DAG)
Type Gq G proteins activate phospholipase C
This enzyme creates two second messengers from
the
double-phosphorylated
membrane
phospholipid
phosphatidylinositol
bisphosphate (PIP2), i.e., inositol 1,4,5trisphosphate (IP3) and diacylglycerol (DAG)
IP3, which is soluble, migrates to the ER, where it
opens Ca2+ channels that allow Ca2+ to flow into
the cytoplasm.
DAG, which is lipophilic, remains in the
membrane, where it activates PK-C
PK-C phosphorylate proteins in the presence of
Ca2+ ions and thereby pass the signal on
Calcium (Ca2+)
METABOLISM:
The concentration of Ca2+ ions in the cytoplasm is
kept down by ATP driven Ca2+ pumps and Na+/Ca2+
exchangers
Many proteins in the cytoplasm and organelles
bind calcium and act as Ca2+ buffers.
Specific signals (e.g., an action potential or
second messenger such as IP 3 or cAMP) trigger a
sudden increase in the cytoplasmic Ca 2+ level
Ca2+ level always only rises very briefly (Ca 2+
spikes), as prolonged high concentrations in the
cytoplasm have cytotoxic effects
Calcium (Ca2+)
ACTION:
Mediated by special Ca2+-binding proteins/ sensors;
include the annexins, calmodulin, and troponin C (in
muscle)
Calmodulin is a small protein (17 kDa) that occurs in all
animal cells
Binding of four Ca2+ ions converts it into a regulatory
element
Ca2+-calmodulin enters into interaction with other proteins
and modulates their properties
Using this mechanism, Ca2+ ions regulate the activity of
enzymes, ion pumps, and components of the cytoskeleton
Thank you
