Covarrubias M, Rubin E
Department of Pathology and Cell Biology, Jefferson Medical College, Philadelphia, PA 19107.
Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6957-60. doi: 10.1073/pnas.90.15.6957.
There is presently a debate regarding the relative merits of lipid-based and protein-based theories of anesthesia and the action of ethanol in the central nervous system. Voltage-sensitive K+ channels play a key role as regulators of neuronal electrical activity and are potential targets of ethanol and other anesthetic agents. We investigated the action of low concentrations of ethanol on four structurally homologous cloned K+ channels expressed in Xenopus oocytes. We report that only the Drosophila Shaw2 channel, which does not inactivate upon prolonged depolarization, is rapidly and reversibly blocked by ethanol in a concentration-dependent manner (17-170 mM). The concentration dependence of the blockade can be explained by assuming a bimolecular interaction between ethanol and the channel. We also found that Shaw2 K+ channels were selectively blocked by halothane (1 mM). Our results support the "protein hypothesis" of ethanol and anesthetic action. These findings open ways to elucidate directly the molecular mechanism of interaction between general anesthetics and a voltage-sensitive K+ channel.
目前，关于麻醉的脂质理论和蛋白质理论以及乙醇在中枢神经系统中的作用的相对优点存在争议。电压敏感性钾通道作为神经元电活动的调节因子发挥着关键作用，并且是乙醇和其他麻醉剂的潜在靶点。我们研究了低浓度乙醇对非洲爪蟾卵母细胞中表达的四种结构同源的克隆钾通道的作用。我们报告称，只有果蝇Shaw2通道在长时间去极化后不会失活，它会被乙醇以浓度依赖的方式（17 - 170 mM）快速且可逆地阻断。通过假设乙醇与通道之间存在双分子相互作用，可以解释这种阻断的浓度依赖性。我们还发现Shaw2钾通道被氟烷（1 mM）选择性阻断。我们的结果支持乙醇和麻醉作用的“蛋白质假说”。这些发现为直接阐明全身麻醉剂与电压敏感性钾通道之间相互作用的分子机制开辟了道路。
