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

To determine whether G proteins activate cardiac ATP-sensitive K+ (K-A TP) channels by regulating intracellular ATP (ATP(i))-dependent gating , currents were measured in inside-out patches. When ATP(i) closed K-A TP channels, activators of endogenous G proteins, GTP (plus adenosine or acetylcholine), GTP gamma S, or AlF4- stimulated channels, an effec t prevented by GDP beta S. In the absence of ATP(i), G protein activat ors were ineffective. Intracellular nucleoside diphosphates restored K -ATP channel openings after the ''rundown'' of spontaneous activity. O nly when ATP(i) suppressed nucleoside diphosphate-induced openings, GT P gamma S or AlF4- enhanced K-ATP channel activity. Active forms of ex ogenous 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 inh ibitory gating. Regulation of ligand-dependent gating represents a dis tinct type of G protein modulation of ion channels.