Inhibition of an inwardly rectifying K^+ channel by G-protein ɑ-subunits

CHOLINERGIC muscarinic, serotonergic, opioid and several other G-protein-coupled neurotransmitter receptors activate inwardly rectifying K^+ channels of the GIRK family, slowing the heartbeat and decreasing the excitability of neuronal cells. Inhibitory modulation of GIRKs by G-protein-coupled receptors may have important implications in cardiac and brain physiology. Previously G_α and G_(βγ) subunits of heterotrimeric G proteins have both been implicated in channel opening, but recent studies attribute this role primarily to the G_(βγ) dimer that activates GIRKs in a membrane-delimited fashion, probably by direct binding to the channel protein. We report here that free GTPγS-activated G_(αil), but not G_(αi2) or G_(αi3), potently inhibits G_(β1γ2)-induced GIRK activity in excised membrane patches of Xenopus oocytes expressing GIRK1. High-affinity but partial inhibition is produced by G_(αs)-GTPγS. G_(αil)-GTPγS also inhibits G_(βlγ2)-activated GIRK in atrial myocytes. Antagonistic interactions between G_α and G_(βγ) may be among the mechanisms determining specificity of G protein coupling to GIRKs