EVIDENCE THAT THE NUCLEOTIDE EXCHANGE AND HYDROLYSIS CYCLE OF G-PROTEINS CAUSES ACUTE DESENSITIZATION OF G-PROTEIN GATED INWARD RECTIFIER K+ CHANNELS

The G-protein gated inward rectifier K+ channel (GIRK) is activated in vivo by the G beta gamma subunits liberated upon G(i)-coupled recepto r activation. We have recapitulated the acute desensitization of recep tor-activated GIRK currents in heterologous systems and shown that it is a membrane-delimited process. Its kinetics depends on the guanine n ucleotide species available and could be accounted for by the nucleoti de exchange and hydrolysis cycle of G proteins. Indeed, acute desensit ization is abolished by nonhydrolyzable GTP analogues. Whereas regulat ors of G-protein signaling (RGS) proteins by their GTPase-activating p rotein activities are regarded as negative regulators, a positive regu latory function of RGS4 is uncovered in our study; the opposing effect s allow RGS4 to potentiate acute desensitization without compromising GIRK activation.