G-protein signaling G-Protein alpha-s signaling cascades

G-Protein alpha-s signaling cascades

G-protein alpha-s coupled receptors interact with trimericG-protein alpha-s/ beta/gamma causing exchange of GDP for GTP bound toG-protein alpha-s subunits, followed by dissociation of the beta/gammaheterodimers.

G-protein alpha-s can directly stimulate activity of v-srcsarcoma (Schmidt-Ruppin A-2) viral oncogene homolog ( c-Src ) and Adenylatecyclase 1 ( Adenylate cyclase type I ) .

Regulators of G-protein signaling (RGS) proteins are GTPase-activatingproteins (GAPs) that attenuate signaling by heterotrimeric G proteins. Regulator ofG-protein signaling 2, 24kDa ( RGS2 ) directly binds with G-protein alpha-sand selectively inhibits G protein alpha-s function [1].

G-protein alpha-s activates all isoforms of adenylate cyclases.After stimuli, Adenylate cyclase type I increases levels of cAMP in thecell and activates Protein kinase, cAMP-dependent ( PKA ) inactive complex (PKA-reg (cAMP-dependent) - PKA-cat (cAMP-dependent) ), which results in PKAactivation [2].

PKA regulates activity of different proteins participating in various cellprocesses.

PKA-cat (cAMP-dependent) phosphorylates and stimulates cAMP responsive elementbinding protein 1 ( CREB1 ) [3]. Phosphorylation of phosphodiesterase4A, cAMP-specific ( PDE4A) by PKA-cat (cAMP-dependent) increasesPDE4A activity and catalyzes cAMP hydrolysis [4]. PKA-cat(cAMP-dependent) also phosphorylates Ryanodine receptor 1 ( RYR1 ) and,thereby, activates a calcium (Ca2+) release channel [5]. 

On the other hand, phosphorylation by PKA inhibits Glycogen synthasekinase-alpha/beta ( GSK3alpha/beta ) activity [6], reduces theaffinity of Adducin 1 ( Alpha adducin ) for actin complexes, and blocks the actionof Anaphase-promoting complex (APC), which regulates mitotic progression andchromatin assembly [7].

Other targets for cAMP are guanine nucleotide exchange factors for smallGTPases. cAMP binds guanine nucleotide exchange factor Rap guanine nucleotideexchange factor (GEF) 2 ( PDZ-GEF1 ) and activates Mitogen-activated proteinkinase kinases 1 and 2 ( MEK1(MAP2K1), MEK2(MAP2K2) )/ Mitogen-activatedprotein kinases 1-3 ( ERK1/2 ) pathway via v-Ha-ras Harvey rat sarcoma viraloncogene homolog ( H-RAS )- v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1 ) regulation [8].

Other cAMP-binding guanine nucleotide exchange factors Rap guanine nucleotide exchangefactor (GEF) 4 and 3 ( cAMP-GEFII, cAMP-GEFI ) promote cell proliferationvia RAP1A, member of RAS oncogene family ( RAP-1A )/ v-raf murine sarcoma viraloncogene homolog B1 ( B-RAF )/ MEK1(MAP2K1), MEK2(MAP2K2)/ERK1/2 pathway and inhibit c-Raf-1 signaling [9].

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