MOLECULAR DETERMINANTS OF STATE-DEPENDENT BLOCK OF NA+ CHANNELS BY LOCAL-ANESTHETICS
MOLECULAR DETERMINANTS OF STATE-DEPENDENT BLOCK OF NA+ CHANNELS BY LOCAL-ANESTHETICS
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DOI：
10.1126/science.8085162
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发表时间：
1994-09-16
期刊：
影响因子：
56.9
通讯作者：
CATTERALL, WA
中科院分区：
文献类型：
--
作者：
RAGSDALE, DS;MCPHEE, JC;CATTERALL, WA
钠离子（Na+）通道启动电兴奋细胞的动作电位，是局部麻醉药物的分子靶点。在爪蟾卵母细胞中表达时，大鼠脑Na+通道α亚基结构域IV的跨膜片段S6中的定点突变选择性地修饰了药物与静息或开放和失活通道的结合。突变F1764A，靠近这一段的中间，开放和失活通道的亲和力降低到野生型值的1%，导致几乎完全消除药物阻滞的使用依赖性和电压依赖性，而突变N1769A增加了静息通道的亲和力15倍。突变I1760A为药物分子从细胞外侧到达受体位点创建了一个通路。结果定义的位置的局部麻醉剂受体网站的孔的Na+通道，并确定分子决定因素的状态依赖性结合的局部麻醉剂。
Sodium ion (Na+) channels, which initiate the action potential in electrically excitable cells, are the molecular targets of local anesthetic drugs. Site-directed mutations in transmembrane segment S6 of domain IV of the Na+ channel alpha subunit from rat brain selectively modified drug binding to resting or to open and inactivated channels when expressed in Xenopus oocytes. Mutation F1764A, near the middle of this segment, decreased the affinity of open and inactivated channels to 1 percent of the wild-type value, resulting in almost complete abolition of both the use-dependence and voltage-dependence of drug block, whereas mutation N1769A increased the affinity of the resting channel 15-fold. Mutation I1760A created an access pathway for drug molecules to reach the receptor site from the extracellular side. The results define the location of the local anesthetic receptor site in the pore of the Na+ channel and identify molecular determinants of the state-dependent binding of local anesthetics.