G protein-gated inwardly rectifying potassium channels are targets for volatile anesthetics

G protein-gated inwardly rectifying potassium channels (GIRKs) are a family of homo- and hetero-oligomeric K+ channels composed of different subunits (GIRK1 to 4 in mammals). GIRK4 and GIRK1 are found mainly in the atrium, wh ereas neuronal cells predominantly express the GIRK1, GIRK2, and GIRK3 isof orms. When activated, GIRK channels slow the firing rate of atrial myocytes and neuronal cells. Because of their key role in controlling excitability, we investigated the influence of a prototypic anesthetic, halothane, on GI RK channels of different subunit composition expressed in Xenopus laevis oo cytes. Halothane enhanced background currents through hetero-oligomeric GIR K1/GIRK4 and homo-oligomeric GIRK1(F137S) channels but not through homo-oli gomeric GIRK2 channels. This activation of basal current did not depend on the presence of coexpressed G protein-coupled receptors but instead require d the presence of G(beta/gamma) In contrast to basal GIRK currents, the ago nist-induced GN current (via coexpressed m(2) muscarinic receptors) was inh ibited by halothane. For GIRK1/GIRK4 and GIRK1(F137S) channels this inhibit ion was most pronounced at low concentrations of the anesthetic (0.1-0.3 mM ) and occurred also when channels had been activated by guanosine-5'-O-(3-t hio)tri phosphate. This inhibition, however, was overridden by high concent rations of halothane (0.9 mM) and augmentation of the agonist-induced curre nt was observed. This increase in agonist-induced current was never seen wi th GIRK2 homo-oligomeric channels. Agonist-induced currents mediated by GIR K2 channels were always inhibited by halothane with an IC50 value of approx imately 60 muM. These data suggest a direct interaction of halothane with G IRK channels.