ACTIVATION OF THE CLONED MUSCARINIC POTASSIUM CHANNEL BY G-PROTEIN BETA-GAMMA-SUBUNITS

ACETYLCHOLINE released during parasympathetic stimulation of the vagal nerve slows the heart rate through the activation of muscarinic recep tors and subsequent opening of an inwardly rectifying potassium channe l(1) The activation of these muscarinic potassium channels is mediated by a pertussis toxin-sensitive heterotrimeric GTP-binding protein (G protein)(2,3). It has not been resolved whether exogenously applied G( alpha)(4,5) or G(beta gamma)(6,7), Or both, activate the channel. Usin g a heterologous expression system, we have tested the ability of diff erent G protein subunits to activate the cloned muscarinic potassium c hannel, GIRK1(8,9). We report here that coexpression of GIRK1 with G(b eta gamma) but not G(alpha beta gamma) in Xenopus oocytes results in c hannel activity that persists in the absence of cytoplasmic GTP. This activity is reduced by fusion proteins of the beta-adrenergic receptor kinase and of recombinant G(alpha i)-GDP, both of which are known to interact with G(beta gamma)(10,11). Moreover, application of recombina nt G(beta gamma), but not G(alpha i)-GTP-gamma S, activates GIRK1 chan nels. Thus G(beta gamma) appears to be sufficient for the activation o f GIRK1 muscarinic potassium channels.