I-K.ACh activation by arachidonic acid occurs via a G-protein-independent pathway mediated by the GIRK1 subunit

The molecular target of arachidonic-acid-derived metabolites, serving as se cond messengers that activate atrial acetylcholine-activated potassium curr ent (I-K.ACh) in addition to G-protein beta/gamma subunits (G(beta/gamma)), is unknown. Co-expression of two isoforms of C-protein-activated, inwardly rectifying potassium channels (GIRKs) in oocytes of Xenopus laevis reveale d that these heterologous co-expressed GIRKs, which are responsible for the formation of I-K.ACh in the atrium, are activated by arachidonic acid meta bolites, like their counterparts in atrial cells. The expression of homooli gomeric GIRK1(F137S) and GIRK4(wt) channels revealed that this activatory m echanism is specific to the GIRK1 subunit. Sequestrating available G(beta/g amma) by overexpression of C-beta ARK (a G(beta/gamma) binding protein) fai led to abolish the activation of GIRK currents by arachidonic acid. From ou r experiments we conclude that the GIRK1 subunit itself is the molecular ta rget fur regulation of GIRK channels by arachidonic acid metabolites.