Identification of a binding site of general anesthetics on the tandem pore domain potassium channels

ERG 1、ELK 1和KCNQ 2/3电压门控钾通道对所有测试的全身麻醉剂（氟烷、异氟烷、恩氟烷、F3、F6、戊巴比妥、丙泊酚、依托咪酯、阿法沙龙、氯胺酮、乙醇和己醇）的2个最小肺泡浓度（MAC）具有抗性。另一方面，在内向整流钾通道中，GIRK通道被挥发性麻醉药抑制，但不被静脉麻醉药抑制。神经元型GIRK 1/2通道被2 MAC的氟烷、异氟烷、安氟烷和F3抑制，而心脏型GIRK 1/4通道仅被F3抑制。相反，IRK 1和ROMK 1通道对所有测试的麻醉剂完全耐受。氟烷也能抑制m-阿片受体激活的GIRK 2通道的电流反应。因此，在内向整流钾通道中，GIRK通道，特别是由GIRK 2亚基（神经元亚基）组成的通道，被认为对挥发性麻醉剂敏感。一氧化二氮（0.06大气压）轻微但选择性地增强GIRK通道（GIRK 1/2、GIRK 1/4、GIRK 2通道）约10%。由μ-阿片受体激活的GIRK 2通道也被一氧化二氮增强。嵌合和多个氨基酸突变的结果表明，该地区含有跨膜结构域，但不是孔形成结构域，可能参与确定GIRK和IRK通道之间的麻醉敏感性的差异。虽然麻醉剂对GIRK通道功能的抑制不太可能解释麻醉作用，但它可能导致一些兴奋性副作用。

The ERG1,ELK1,and KCNQ2/3 voltage-gated potassium channels were resistant to 2 minimum alveolar concentrations(MAC) of all general anesthetics tested(halothane, isoflurane, enflurane, F3,F6,pentobarbital, propofol, etomidate, alphaxalone, ketamine, ethanol, and hexanol). On the other hand, among inwardly rectifying potassium channels, GIRK channels were inhibited by volatile anesthetics, but not by intravenous anesthetics. The neuronal-type GIRK1/2 channels were inhibited by 2 MAC of halothane, isoflurane, enflurane, and F3, whereas the cardiac-type GIRK1/4 channels were inhibited only by F3. Conversely, IRK1 and ROMK1 channels were completely resistant to all anesthetics tested. Current responses of GIRK2 channels activated by m-opioid receptors were also inhibited by halothane. Thus, among inwardly rectifying potassium channels, GIRK channels, especially those composed of the GIRK2 subunit(neuronal subunit), are suggested to be sensitive to volatile anesthetics. Nitrous oxide (〜0.6 atmosphere) slightly but selectively potentiated GIRK channels(GIRK1/2,GIRK1/4, GIRK2 channels) by 〜10%. GIRK2 channels activated by mu-opioid receptors were also potentiated by nitrous oxide. Results of chimeric and multiple amino acid mutations suggest that the region containing the trans membrane domains, but not the pore-forming domain, may be involved in determining differences in anesthetic sensitivity between GIRK and IRK channels. Although inhibition of GIRK channel function by anesthetics is unlikely to account for the anesthetic actions, it may contribute to some excitatory side effects.