Gating kinetics of Shaker K+ channels are differentially modified by general anesthetics

TheShakerBK⁺ channel was used as a modelvoltage-gated channel to probe the interaction of volatile generalanesthetics with gating mechanisms. The effects of three anesthetics,chloroform (CHCl₃), isoflurane,and halothane, were studied using recombinant native and mutantShaker channels expressed inXenopus oocytes. Gating currents andmacroscopic ionic currents were recorded with the cut-open oocytevoltage-clamp technique. The effects ofCHCl₃ and isoflurane on gatingkinetics of noninactivating mutants were opposite, whereas halothanehad no effect. The effects on ionic currents were also agent dependent:CHCl₃ and halothane produced areduction of the macroscopic conductance, whereas isoflurane increasedit. The results indicate that the gating machinery of the channel ismostly insensitive to the anesthetics during activation until near theopen state. The effects on the conductance are mainly due to changes inthe transitions in and out of the open state. The data give support todirect protein-anesthetic interactions. The magnitude and nature of theeffects invite reconsideration ofShaker-likeK⁺ channels as important sites ofaction of general anesthetics.