Research ArticleG Proteins

RGS Proteins Maintain Robustness of GPCR-GIRK Coupling by Selective Stimulation of the G Protein Subunit Gαo

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Science Signaling  21 Feb 2012:
Vol. 5, Issue 212, pp. ra15
DOI: 10.1126/scisignal.2002202

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Balancing Activation and Inactivation

Members of the RGS (regulator of G protein signaling) family of proteins stimulate the intrinsic guanosine triphosphatase (GTPase) activity of G proteins downstream of G protein–coupled receptors (GPCRs) to accelerate the termination of their activity. RGS proteins have therefore generally been viewed as negative regulators of G protein signaling. Consequently, it seems surprising that RGS proteins not only accelerate the deactivation of GPCR-coupled K+ currents (GIRK currents) but also accelerate their activation and increase their amplitude. Chuang and Chuang explored this “RGS paradox” in a Xenopus oocyte expression system and found that RGS4 and RGS8 acted through their RGS box domains (which also mediate their GAP activity) to stimulate Gαo activation, counteracting the inhibitory effect of their GAP activity. Indeed, the stimulatory effect was apparent with injection of smaller amounts of RGS mRNA than were required for the acceleration of channel deactivation. The authors propose that differential modulation of different G protein isoforms by different RGS proteins may enable the fine-tuning of signaling pathways downstream of GPCRs, increasing the repertoire of responses to GPCR activation.

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