G-PROTEINS ACTIVATE ATP-SENSITIVE K+ CHANNELS BY ANTAGONIZING ATP-DEPENDENT GATING

To determine whether G proteins activate cardiac ATP-sensitive K+ (K-ATP) channels by regulating intracellular ATP (ATP(i))-dependent gating, currents were measured in inside-out patches. When ATP(i) closed K-ATP channels, activators of endogenous G proteins, GTP (plus adenosine or acetylcholine), GTP gamma S, or AlF4- stimulated channels, an effect prevented by GDP beta S. In the absence of ATP(i), G protein activators were ineffective. Intracellular nucleoside diphosphates restored K-ATP channel openings after the ''rundown'' of spontaneous activity. Only when ATP(i) suppressed nucleoside diphosphate-induced openings, GTP gamma S or AlF4- enhanced K-ATP channel activity. Active forms of exogenous G protein subunits (G(alpha i-1), G(alpha i-2), or G(alpha o)) activated only K-ATP channels closed by ATP(i). G proteins stimulate cardiac K-ATP channels apparently by antagonizing ATP(i)-dependent inhibitory gating. Regulation of ligand-dependent gating represents a distinct type of G protein modulation of ion channels.