Halothane inhibits an intermediate conductance Ca2+-activated K+ channel by acting at the extracellular side of the ionic pore

Background: Actions of volatile anesthetics on ligand-gated ion channels, such as γ-aminobutyric acid type A receptors, have been studied extensively. However, actions on other types of channels, such as K + channels, are poorly understood. The authors previously showed that a Ca 2+ -activated K + channel, IK, is sensitive to halothane, whereas SK1, another Ca 2+ -activated K + channel, is insensitive. To explore how halothane acts on Ca 2+ -activated K + channels, chimeras between IK and SK1 were constructed, and halothane sensitivity was analyzed. Methods: IK, SK1, and chimera channels were expressed in Xenopus laevis oocytes. Currents of expressed channels were measured in the presence of 10 μM Ca 2+ by excised patch clamp analysis. Time constants of inhibition by halothane were compared between inside-out and outside-out patch configurations. Results: Currents from chimera channels possessing the pore domain derived from IK were inhibited by halothane, whereas those possessing the SK1 pore domain were insensitive. Time constants of inhibition by halothane were significantly smaller in the outside-out patches than in the inside-out patches of both wild-type IK and a chimera with pore domain of IK. Conclusions: It is suggested that halothane interacts with the extracellular part of the ionic pore of IK. Whether this type of interaction is involved in the mechanism of anesthetic actions on ligand-gated ion channels warrants further investigation.