RGS proteins maintain robustness of GPCR‐GIRK coupling

Objective To elucidate the mechanism underlying sustained GPCR‐GIRK coupling under RGS actions. Results Regulators of G‐protein signaling (RGS) are GTPase activating proteins (GAP) that reduce response amplitudes of activated G‐protein coupled receptors (GPCRs). We discovered that, although RGS proteins drastically accelerate kinetics of GPCR‐coupled K+ currents (GIRK), they actually increased amplitudes of inhibitory neurotransmitter‐evoked GIRK currents. The RGS‐Box domain alone is sufficient for stimulation of transmitter activation of K+ currents, but its membrane association enhances the efficiency of stimulation. Moreover, RGS4 mutants with compromised GAP activity still augment GPCR‐GIRK coupling. Among the pertussis toxin sensitive G‐proteins, we found that RGS4 selectively stimulates Gαo to maintain robustness of GPCR‐GIRK coupling, by accelerating activation kinetics of Gαo. Conclusion Opposing actions of RGS proteins both stimulate and inhibit G‐proteins to modulate ultimate amplitudes of transmitter‐induced GIRK currents and to differentiate signal intensity coupled to various G‐protein isoforms.