RECOMBINANT G-PROTEIN BETA-GAMMA-SUBUNITS ACTIVATE THE MUSCARINIC-GATED ATRIAL POTASSIUM CHANNEL

ACETYLCHOLINE activates inwardly rectifying potassium channels (I-K.AC h) in the heart(1) through muscarinic receptor binding and activation of pertussis-toxin-sensitive G proteins(2,3). Experiments showing that only the beta gamma-subunit (G beta gamma) activates I-K.ACh (ref. 4) were challenged by reports that only the activated alpha-subunit (G a lpha) was effective(5). Here we examine I-K.ACh regulation using purif ied brain and recombinant G-protein subunits. Six recombinant G beta g amma-subunits activated I-K.ACh with apparent half-maximal activation concentrations of 3-30 nM. Activation of I-K.ACh by recombinant G alph a-GTP gamma S was observed, but this was probably due to release of GT P gamma S from the protein. Importantly, I-K.ACh activity elicited by GTP gamma S was inhibited by purified brain and recombinant G alpha-GD P, suggesting that native G beta gamma plays a major role in this path way. We conclude that G beta gamma is a primary regulator of I-K.ACh a ctivity.