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

串联孔域钾通道上全身麻醉药结合位点的鉴定

基本信息

批准号：
13671567
负责人：
YAMAKURA Tomohiro
金额：
$ 2.3万
依托单位：
NIIGATA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

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.

ERG1、ELK1 和 KCNQ2/3 电压门控钾通道对所有测试的全身麻醉药（氟烷、异氟烷、安氟烷、F3、F6、戊巴比妥、丙泊酚、依托咪酯、阿法沙酮、氯胺酮、乙醇和己醇）的 2 个最低肺泡浓度 (MAC) 具有耐药性。另一方面，在内向整流钾通道中，GIRK通道被挥发性麻醉剂抑制，但不被静脉麻醉剂抑制。神经型 GIRK1/2 通道被氟烷、异氟烷、安氟烷和 F3 的 2 MAC 抑制，而心脏型 GIRK1/4 通道仅被 F3 抑制。相反，IRK1 和 ROMK1 通道对所有测试的麻醉剂完全具有抵抗力。 m-阿片受体激活的 GIRK2 通道的当前反应也被氟烷抑制。因此，在内向整流钾通道中，GIRK通道，特别是由GIRK2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（约 0.6 个大气压）轻微但选择性地增强 GIRK 通道（GIRK1/2、GIRK1/4、GIRK2 通道）约 10%。 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，包含跨膜结构域而不是成孔结构域的区域可能参与决定 GIRK 和 IRK 通道之间麻醉敏感性的差异。尽管麻醉药对 GIRK 通道功能的抑制不太可能解释麻醉作用，但它可能会导致一些兴奋性副作用。