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

Abstract

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, whereas neuronal cells predominantly express the GIRK1, GIRK2, and GIRK3 isoforms. 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 GIRK channels of different subunit composition expressed in Xenopus laevis oocytes. Halothane enhanced background currents through hetero-oligomeric GIRK1/GIRK4 and homo-oligomeric GIRK1(F137S) channels but not through homo-oligomeric GIRK2 channels. This activation of basal current did not depend on the presence of coexpressed G protein-coupled receptors but instead required the presence of G(beta/gamma). In contrast to basal GIRK currents, the agonist-induced GIRK current (via coexpressed m2 muscarinic receptors) was inhibited by halothane. For GIRK1/GIRK4 and GIRK1(F137S) channels this inhibition 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-thio)triphosphate. This inhibition, however, was overridden by high concentrations of halothane (0.9 mM) and augmentation of the agonist-induced current was observed. This increase in agonist-induced current was never seen with GIRK2 homo-oligomeric channels. Agonist-induced currents mediated by GIRK2 channels were always inhibited by halothane with an IC(50) value of approximately 60 microM. These data suggest a direct interaction of halothane with GIRK channels.