Research ArticleG Proteins

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

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

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Abstract

Termination of heterotrimeric guanine nucleotide–binding protein (G protein) signaling downstream of activated G protein–coupled receptors (GPCRs) is accelerated by regulator of G protein signaling (RGS) proteins, which act as guanosine triphosphatase (GTPase)–activating proteins (GAPs). Using a Xenopus oocyte expression system, we found that although RGS proteins had a negative effect of accelerating the kinetics of GPCR-coupled potassium ion (K+) channel (GIRK) deactivation, they also had positive effects of increasing the amplitudes and activation kinetics of neurotransmitter-evoked GIRK currents. The RGS box domain alone was sufficient to stimulate neurotransmitter-dependent activation of GIRK currents. Moreover, RGS4 mutants with compromised GAP activity augmented GPCR-GIRK coupling (as assessed by measurement of the GIRK current elicited by neurotransmitter). By accelerating G protein activation kinetics, RGS4 specifically stimulated Gαo, which stimulated GPCR-GIRK coupling despite its GAP activity. Opposing actions of RGS proteins thus both stimulate and inhibit G proteins to modulate the amplitude and kinetics of neurotransmitter-induced GIRK currents, thereby distinguishing the responses to activation of different G protein isoforms.

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