Gαi controls the gating of the G protein-activated K+ channel, GIRK

GIRK (Kir3) channels are activated by neurotransmitters; coupled to G proteins, via a direct binding of Gbetagamma. The role of Galpha subunits in GIRK gating is elusive. Here we demonstrate that Galpha(i) is not only a donor of Gbetagamma but also regulates GIRK gating. When overexpressed in Xenopus oocytes, GIRK channels show excessive basal activity and poor activation by agonist or Gbetagamma. Coexpression of Galpha(i3) or Galpha(i1), restores the correct gating parameters. Galpha(i) acts neither as a pure Gbetagamma scavenger nor as an allosteric cofactor for Gbetagamma. It inhibits only the basal activity without interfering with Gbetagamma-induced response. Thus, GIRK is regulated, in distinct ways, by both arms of the G protein. Gal probably acts in its GDP bound form, alone or as a part of Galphabetagamma heterotrimer.