Activation of G protein-coupled inward rectifier K+ channels in brain neurons requires association of G protein beta gamma subunits with cell membrane

In cultured noradrenergic neurons from the rat locus coeruleus, application of recombinant G protein beta(1) gamma(2) subunits (30 nM) to the cytoplasmic side induced single channel activity similar to the somatostatin-induced single channel activity of G protein-coupled inward rectifier potassium channels (K-ir (G)). In contrast, recombinant GTP gamma S-activated, myristoylated alpha(i2) (100 nM) did not activate this brain K-ir (G). Application of beta(1) gamma(2)C68S (30 nM or 150 nM), in which the cysteine residue fourth from the carboxyl terminus of gamma 2 was replaced by serine, failed to activate the brain K-ir(G). This mutant lacks prenylation which is required for the association of beta gamma subunit with the cell membrane, Thus, our results suggest that the association of beta gamma subunit with the cell membrane is a prerequisite for activating K-ir(G) channels.