SODIUM-CHANNEL MUTATIONS IN PARAMYOTONIA-CONGENITA UNCOUPLE INACTIVATION FROM ACTIVATION
SODIUM-CHANNEL MUTATIONS IN PARAMYOTONIA-CONGENITA UNCOUPLE INACTIVATION FROM ACTIVATION
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DOI：
10.1016/0896-6273(94)90271-2
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发表时间：
1994-02-01
期刊：
影响因子：
16.2
通讯作者：
HORN, R
中科院分区：
文献类型：
--
作者：
CHAHINE, M;GEORGE, AL;HORN, R
成人骨骼肌Na+通道亚基突变导致先天性肌副张力症。R1448H和R1448C两种先天性肌张力副缩突变在4结构域S4段用组氨酸和半胱氨酸代替精氨酸。这些突变，在细胞系中表达，对Na+电流的激活只有很小的影响，但突变通道比野生型通道失活得更慢，电压依赖性更小，并且从失活中恢复的速度更快。胞外pH值的升高使R1448H的失活速率与R1448C相似，表明该残基位于胞外，其电荷对正常失活很重要。对单通道数据的分析表明，突变通道在关闭状态下正常失活，但在打开状态下失活。这些数据表明结构域4的S4螺旋在激活和失活之间的耦合中起着关键作用。
Mutations in the adult human skeletal muscle Na+ channel a subunit cause the disease paramyotonia congenita. Two paramyotonia congenita mutations, R1448H and R1448C, substitute histidine and cysteine for arginine in the S4 segment of domain 4. These mutations, expressed in a cell line, have only small effects on the activation of Na+ currents, but mutant channels inactivate more slowly with less voltage dependence than wild-type channels and exhibit an enhanced rate of recovery from inactivation. Increase of extracellular pH made the rate of inactivation of R1448H similar to that of R1448C, suggesting that this residue has an extracellular location and that its charge is important for normal inactivation. Analysis of single-channel data reveals that mutant channels inactivate normally from closed states, but poorly from the open state. The data suggest a critical role for the S4 helix of domain 4 in coupling between activation and inactivation.