RGS proteins maintain robustness of GPCR-GIRK coupling by selective stimulation of the G protein subunit Gαo

Science Signaling
Huai-hu Chuang, Alexander Y Chuang

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 Gα₀, 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 pr...Continue Reading

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