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Signal transduction cAMP signaling


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Signal transduction cAMP signaling

cAMP Signaling

Adenylate cyclases ( AC s)  are a family ofenzymes that produce cyclic AMP ( cAMP ) from ATP upon extracellular stimulation.To date, at least 9 membrane-bound AC s have been isolated and characterized.Intracellular signaling via cAMP generates downstream effects that range fromchanges in the function of ion channels to changes in intracellular energy metabolism andgene transcription [1].

Adenylate cyclases are capable of integrating positive and negative signalsthat act directly from G protein-coupled receptors ( GPCR s) through stimulationof the G-protein alpha and beta/gamma subunits or indirectly viaintracellular signaling by protein kinases: Protein kinase A ( PKA ),Calcium/calmodulin-dependent protein kinase ( CaMK ), and Protein kinase C (PKC ).

Stimulation through G-protein alpha-s is the major mechanism, by whichAC s are activated and cAMP levels are elevated. Whereas all isoforms ofAC s are potentially activated by G-protein alpha-s -coupled receptors, theinhibition by G-protein alpha-i family -coupled receptors appears to be isozymespecific. G-protein alpha-i family acts as a noncompetitive inhibitor ofG-protein alpha-s -stimulated Adenylate cyclases 1, 5 and 6 ( Adenylate cyclasetype I, Adenylate cyclase type V and Adenylate cyclase type VI ), anddecreases level of cAMP [2]. G-proteins beta/gamma subunitsstimulate Adenylate cyclases 2, 4 and 7 ( Adenylate cyclase type II, Adenylatecyclase type IV and Adenylate cyclase type VII ) and inhibit Adenylatecyclase type I, Adenylate cyclase type V and Adenylate cyclase typeVI.

Adenylate cyclases type I, II, III, V, VI and VII have been shown to bedirectly phosphorylated by PKC isoenzymes. Adenylate cyclase type V isphosphorylated and activated by Protein kinase C alpha and zeta ( PKC-alpha,PKC-zeta ); Adenylate cyclase type II - by PKC-alpha; Adenylatecyclase type VII - by Protein kinase C delta ( PKC-delta ). Adenylatecyclase type VI is phosphorylated and inhibited by PKC. Adenylate cyclasestype I is phosphorylated and inhibited by Calcium/calmodulin-dependent protein kinaseIV ( CaMK IV ), Adenylate cyclases type III is phosphorylated and inhibitedby Calcium/calmodulin-dependent protein kinase (CaM kinase) II ( CaMK II ).Adenylate cyclases type IX is indirectly inhibited by Ca('2+) via theactivation of Calcineurin [2].

PKA is a significant target of cAMP. PKA consist of Protein kinase,cAMP-dependent, regulatory ( PKA-reg (cAMP-dependent) ) and catalytic ( PKA-cat(cAMP-dependent) ) subunits. PKA-reg (cAMP-dependent bind and inhibit thePKA-cat (cAMP-dependent). cAMP molecules bind to each regulatory subunit,eliciting a reversible conformational change that releases active catalytic subunits[3]. PKA directly phosphorylates and inhibits Adenylate cyclasestype V and IV, realizing feedback regulation.

PKA also phosphorylates and stimulates cAMP responsive element binding protein1 ( CREB1 ) [4], Ryanodine receptor 1 ( RYR1 ) [5], Lipase, hormone-sensitive ( LIPS ) [6], Phosphorylasekinase, alpha ( PHK alpha ), P hospholamban, KDEL (Lys-Asp-Glu-Leu)endoplasmic reticulum protein retention receptors ( KDELR ), and inhibits Glycogensynthase kinase-alpha/beta ( GSK3alpha/beta ) [7].

Other targets for cAMP are guanine nucleotide exchange factors (GEFs) thatmodulate activity of small GTPases. cAMP binding to Rap guanine nucleotideexchange factors (GEF) 3 and 4 ( cAMP-GEFI and cAMP-GEFII ) activate RAP1Aand RAP2A, members of RAS oncogene family ( RAP-1A and RAP-2A) pathways,respectively [8], [9].