title: Evidence that the nucleotide exchange and hydrolysis cycle of G proteins causes acute desensitization of G-protein gated inward rectifier K+ channels.
abstract: The G-protein gated inward rectifier K+ channel (GIRK) is activated in vivo by the Gbeta gamma subunits liberated upon Gi-coupled receptor activation. We have recapitulated the acute desensitization of receptor-activated GIRK currents in heterologous systems and shown that it is a membrane-delimited process. Its kinetics depends on the guanine nucleotide species available and could be accounted for by the nucleotide exchange and hydrolysis cycle of G proteins. Indeed, acute desensitization is abolished by nonhydrolyzable GTP analogues. Whereas regulators of G-protein signaling (RGS) proteins by their GTPase-activating protein activities are regarded as negative regulators, a positive regulatory function of RGS4 is uncovered in our study; the opposing effects allow RGS4 to potentiate acute desensitization without compromising GIRK activation.
authors.affiliation: Departments of Physiology and Biochemistry, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Chuang
authors.forename: M
authors.initials: M
authors.lastname: Yu
authors.forename: Y N
authors.initials: YN
authors.lastname: Jan
authors.forename: L Y
authors.initials: LY
authors.lastname: Jan
mesh_terms: D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006150:Guanine Nucleotides / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D015640:Ion Channel Gating; D007700:Kinetics; D008954:Models, Biological; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D011506:Proteins / Q000378:metabolism; D020710:RGS Proteins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D006150:Guanine Nucleotides; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011506:Proteins; D020710:RGS Proteins; D011956:Receptors, Cell Surface; D006153:Guanosine Diphosphate; C098799:RGS4 protein; D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins