title: RGS proteins maintain robustness of GPCR-GIRK coupling by selective stimulation of the G protein subunit Gαo.
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 protein isoforms.
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA. huai-hu.chuang@cornell.edu
authors.forename: Huai-hu
authors.initials: HH
authors.lastname: Chuang
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Chuang
mesh_terms: D000818:Animals; D004594:Electrophysiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D007700:Kinetics; D018377:Neurotransmitter Agents / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014981:Xenopus
chemical_list: D018377:Neurotransmitter Agents; D015221:Potassium Channels; D020710:RGS Proteins; D043562:Receptors, G-Protein-Coupled; C098799:RGS4 protein; D019206:GTP-Binding Protein alpha Subunits, Gi-Go