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

ERG1、ELK1和KCNQ2/3电压门控钾通道对所有受试全身麻醉药(氟烷、异氟烷、安氟醚、F3、F6、戊巴比妥、异丙酚、依托咪酯、α-酮、氯胺酮、乙醇和正己醇)的2种最低肺泡浓度(MAC)具有抗性。另一方面，在内向整流性钾通道中，GIRK通道可被挥发性麻醉剂抑制，但不被静脉麻醉剂抑制。神经元型GIRK1/2通道可被氟烷、异氟醚、安氟醚和F3的2MAC所抑制，而心脏型GIRK1/4通道仅被F3所抑制。相反，IRK1和ROMK1通道对所有测试的麻醉剂都完全耐药。氟烷也抑制由m-阿片受体激活的GIRK2通道的电流反应。因此，在内向整流钾通道中，GIRK通道，尤其是由GIRK2亚单位(神经元亚单位)组成的通道，可能对挥发性麻醉药敏感。一氧化二氮(~0.6大气压)对GIRK通道(GIRK1/2、GIRK1/4、GIRK2通道)有轻微但选择性的增强作用约10%。被Mu阿片受体激活的GIRK2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，包含跨膜结构域的区域可能参与了决定GIRK和IRK通道之间麻醉敏感性差异的区域，而不是形成孔的区域。虽然麻醉药对GIRK通道功能的抑制不太可能是麻醉作用的原因，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.