Inhibition of a G(i)-activated potassium channel (GIRK1/4) by the G(q)-coupled m1 muscarinic acetylcholine receptor

The G protein-coupled inwardly rectifying K+ channel, GIRK1/GIRK4, can be a ctivated by receptors coupled to the G alpha (i) subunit. An opposing role for G alpha (q) receptor signaling in GIRK regulation has only recently beg un to be established. We have studied the effects of mi muscarinic acetylch oline receptor (mAChR) stimulation, which is known to mobilize calcium and activate protein kinase C (PKC) by a G alpha (q)-dependent mechanism, on wh ole cell GIRK1/4 currents in Xenopus oocytes. We found that stimulation of the mi mAChR suppresses both basal and dopamine 2 receptor-activated GIRK 1 /4 currents. Overexpression of G beta gamma subunits attenuates this effect , suggesting that increased binding of G beta gamma to the GIRK channel can effectively compete with the G(q) mediated inhibitory signal. This G(q) si gnal requires the use of second messenger molecules; pharmacology implicate s a role for PKC and Ca2+ responses as mi mAChR-mediated inhibition of GIRK channels is mimicked by PMA and Ca2+ ionophore A23187. We have analyzed a series of mutant and chimeric channels suggesting that the GIRK4 subunit is capable of responding to G(q) signals and that the resulting current inhib ition does not occur via phosphorylation of a canonical PKC site on the cha nnel itself.