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PERTUSSIS TOXIN
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Protein Kinase
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? In prokaryotic cells, cAMP binds to a specific protein
called catabolite regulatory protein (CRP) that binds
directly to DNA and influences gene expression.
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? By contrast, in eukaryotic cells, cAMP binds to a protein
kinase called protein kinase A (PKA), a heterotetrameric
molecule consisting of two regulatory subunits (R) that
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inhibit the activity of the two catalytic subunits (C) whenbound as a tetrameric complex.
? cAMP binding to the R2 C2 tetramer results in the
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following reaction:?
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? The R2 C2 complex has no enzymatic activity, but
the binding of cAMP by R induces dissociation of
the R?C complex, thereby activating the latter.
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? The active C subunit catalyzes the transfer of the
phosphate of ATP to a serine or threonine residue in
a variety of proteins.
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? Protein phosphorylation is now recognized as being
a major and ubiquitous regulatory mechanism.
? The effects of cAMP in
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eukaryotic cells are all
thought to be mediated by
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- carbohydrate and fatprotein phosphorylation-
metabolism,
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dephosphorylation,
- enzyme induction
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principally on serine and- Gene regulation,
threonine residues.
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- synaptic transmission, and
-
cell
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growth
and
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? The control of any of thereplication,
effects
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of
cAMP,
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could be conferred by aincluding such diverse
specific protein kinase,
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processes as
by a specific phosphatase,
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? steroidogenesis,or by specific substrates
? secretion,
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for phosphorylation
? ion transport
? The array of specific
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substrates define a target tissue,
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and are involved in defining the extent of a particularresponse within a given cell.
? For example, the effects of cAMP on gene
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transcription are mediated by CREB, the cyclic AMPresponse element binding protein.
? CREB binds to a cAMP responsive DNA enhancer
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element (CRE) in its nonphosphorylated state and is aweak activator of transcription.
? When phosphorylated by PKA, CREB binds the
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coactivator CREB-binding protein CBP/p300 and as aresult is a much more potent transcription activator.
? CBP and the related p300 contain histone
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acetyltransferase activities, and hence serve as
chromatin-active transcriptional coregulators.
? Interestingly, CBP/p300 can also acetylate certain
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transcription factors thereby stimulating their ability
to bind DNA and modulate transcription.
Phosphodiesterases
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? Actions caused by hormones that increase cAMPconcentration can be terminated in a number of ways,
including the hydrolysis of cAMP to 5-AMP by
phosphodiesterases
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? Phosphodiesterases are subject to regulation by their
substrates, cAMP and cGMP; by hormones; and by
intracellular messengers such as calcium, probably
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acting through calmodulin.? Inhibitors of phosphodiesterase, most notably
methylated xanthine derivatives such as caffeine,
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increase intracellular cAMP and mimic or prolong theactions of hormones through this signal
cGMP :an Intracellular Signal
? Cyclic GMP is made from GTP by the enzyme
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guanylyl cyclase, which exists in soluble and
membrane-bound forms.
? Each of these enzyme forms has unique physiologic
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properties
? The atriopeptins, a family of peptides produced in
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cardiac atrial tissues, cause natriuresis, diuresis,vasodilation, and inhibition of aldosterone secretion.
? These peptides (eg, atrial natriuretic factor) bind to
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and activate the membrane-bound form of guanylylcyclase
? This results in an increase of
cGMP by as much as 50-fold in
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some cases, and this is thought to mediate the effects
mentioned above.
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? A series of compounds, including nitroprusside,nitroglycerin, nitric oxide, sodium nitrite, and sodium azide,
all cause smooth muscle relaxation and are potent
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vasodilators.
? These agents increase cGMP by activating the soluble form
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of guanylyl cyclase, and inhibitors of cGMPphosphodiesterase (the drug sildenafil [Viagra], for example)
enhance and prolong these responses.
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? The increased cGMP activates cGMP-dependent protein
kinase (PKG), which in turn phosphorylates a number of
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smooth muscle proteins leading to relaxation of smoothmuscle and vasodilation.
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