G Proteins

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See related article, pages 1191–1199 Signaling through the activation of G proteins represents the most widely used signaling pathway in mammalian biology.1,2 Classically, a transmembrane receptor comprising seven transmembrane domains (G protein-coupled receptor, GPCR) is activated by an extracellular stimulus and transduces this information to heterotrimeric G proteins through a conformational change of the receptor protein. Throughout evolution, a large variety of GPCRs has evolved to detect a wide spectrum of signals ranging from photons and odorants to endogenous neurotransmitters and hormones such as the catecholamines. Consequently, the majority of currently used drugs act on GPCRs. On receptor-mediated activation of the G protein α-subunit, the bound GDP is exchanged against GTP and both the GTP-bound α-subunit as well as the βγ-subunits may activate downstream targets (Figure). As a GTPase, the α-subunit then rapidly initiates its own inactivation through GTP-hydrolysis. This GTPase cycle of G protein activation and deactivation is subject to regulation by the RGS family of proteins (regulators of G protein signaling) that activate the GTPase function and thereby negatively regulate signaling of GPCRs.3,4 G protein dependent signaling in the cardiovascular system. Classically G proteins are activated through agonist occupied G protein-coupled receptors (GPCRs). In the inactive state, the G protein α-subunit is bound to GDP, with a rapid exchange against GTP on activation. Both the α-subunit and the βγ-subunits can then activate diverse downstream signaling cascades. In addition G protein dependent signaling can be regulated independent from GPCR-activation through activators of G protein signaling (AGS) and nucleoside diphosphate kinase (NDPK). Membrane-bound NDPK B transfers a high energy phosphate onto G β-subunits, which is then transferred onto GDP to form GTP. It thereby localizes GTP-supply to the vincinity of G protein α-subunits and mediates local, receptor-independent activation of G protein α-subunits. It remains to be determined, …