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SECOND MESSENGERS
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Cyclic AMP (cAMP)
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β-adrenergic receptors are coupled to cAMP
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Table 38-2. Properties of the four main classes of mammalian G-protein α-subunits.
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Properties of mammalian G-proteins
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G-protein subfamilyα subunitsMolecular mass (kDa)Toxin substrateTissue distributionEffector
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GiGZ41nonebrain, adrenal medulla, plateletsinhibits adenylate cyclase
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 Gi40pertussis toxinnearly ubiquitousGi α-subunits activate
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 G040pertussis toxinbrain, neural systemsPLC and PLA2 and K+ channels,and inhibit adenylate cyclaseand Ca2+channels
Body_ID: T038002.250
 Gt40pertussis/cholera toxinretinal rods and conesactivates cGMP-phosphodiesterase
Body_ID: T038002.300
 Ggust40pertussis toxintaste budsactivates phosphodiesterase
Body_ID: T038002.350
GsGs44-46cholera toxinubiquitousGs activates adenylatecyclase and Ca2+ channels
Body_ID: T038002.400
 Goll45cholera toxinolfactory neuroepitheliumactivates adenylate cyclase
Body_ID: T038002.450
G12G1244noneubiquitousG12/13 subunits regulate
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 G1344noneubiquitousNa+/H+ exchange, voltage-dependent Ca2+ channels,and eicosanoid signaling
Body_ID: T038002.550
GqGq42nonenearly ubiquitousPLC
Body_ID: T038002.600
 G1142nonenearly ubiquitous 
Body_ID: T038002.650
 G1442nonelung, kidney, liver, spleen, testis 
Body_ID: T038002.700
 G1543nonehemopoietic cells 
Body_ID: T038002.750
 G1644nonehemopoietic cells 
Body_ID: T038002.800
Body_ID: T038002.850
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Some G-proteins can be characterized using different bacterial toxin substrates. PDE, phosphodiesterase; cGMP, cyclic guanosine monophosphate; PLC, phospholipase C; PLA2, phospholipase A2.
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Figure 38.4 Metabolism of cyclic AMP. Adenylyl cyclase catalyzes a cyclization reaction to produce the active cAMP, which is then deactivated by cAMP-phosphodiesterases. cAMP, cyclic adenosineView drug information monophosphate.
β-adrenergic receptors are coupled to the generation of the second messenger, cAMP. The β-adrenergic hormone epinephrineView drug information induces the breakdown of glycogen to glucoseView drug information in muscle and, to a lesser extent, in the liver. In the latter organ, the breakdown of glycogen is predominantly stimulated by the polypeptide hormone glucagon, which is secreted by the pancreas when blood sugar is low (Chapters 12 and 20). One of the earliest signaling events after binding of these hormones to their receptors is the generation of cAMP, a small molecule that has a key role in the regulation of intracellular signal transduction, leading to the conversion of glycogen to glucoseView drug information. cAMP is derived from ATP by the catalytic action of the signaling enzyme, adenylyl cyclase (Fig. 38.4). This cyclization reaction involves the intramolecular attack of the 3'-OH group of the ribose unit on the α-phosphoryl group of ATP to form a phosphodiester bond; this is driven by the subsequent hydrolysis of the released pyrophosphate. The activity of cAMP is terminated by the hydrolysis of cAMP to 5'-AMP by specific cAMP-phosphodiesterases. The importance of cAMP in regulating glycogen breakdown was demonstrated by a series of experiments showing not only that hormones that activate adenylyl cyclase activity in fat cells also stimulate glycogen breakdown, but also that cell-permeant analogs of cAMP, such as dibutyryl cAMP, can mimic the effects of these hormones in inducing glycogen breakdown.
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Adenylyl cyclase is activated by a G-protein
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The β-adrenergic receptor is coupled to adenylyl cyclase activation by the action of the α-subunit of the stimulatory G-protein, called Gs. Because each molecule of bound hormone can stimulate many Gs α-subunits, this form of transmembrane signaling amplifies the original hormone signal. Although hydrolysis of GTP by the intrinsic GTPase of the Gs α-subunit acts to switch off adenylyl cyclase activation, the hormone-receptor complex must also be deactivated to return the cell to its resting, unstimulated state. This receptor desensitization, which occurs after prolonged exposure to the hormone, involves phosphorylation of the C-terminal tail of the hormone-occupied β-adrenergic receptor by a kinase known as β-adrenergic receptor kinase. G-protein-coupled receptors, such as α-adrenergic receptors, which act to inhibit cAMP generation, are coupled to the inhibition of adenylyl cyclase via the inhibitory, Gi-, G-protein.
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