Chahine M, George A L, Zhou M, Ji S, Sun W, Barchi R L, Horn R
Department of Physiology, Jefferson Medical College, Philadelphia, Pennsylvania 19107.
Neuron. 1994 Feb;12(2):281-94. doi: 10.1016/0896-6273(94)90271-2.
Mutations in the adult human skeletal muscle Na+ channel alpha 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.
成人人类骨骼肌钠通道α亚基的突变会导致先天性副肌强直症。两个先天性副肌强直症突变，R1448H和R1448C，在结构域4的S4片段中用组氨酸和半胱氨酸取代了精氨酸。这些在细胞系中表达的突变对钠电流的激活只有很小的影响，但突变通道的失活比野生型通道更慢，电压依赖性更小，并且从失活状态恢复的速率有所增强。细胞外pH值的升高使R1448H的失活速率与R1448C相似，这表明该残基位于细胞外，并且其电荷对正常失活很重要。单通道数据分析表明，突变通道从关闭状态正常失活，但从开放状态失活较差。数据表明结构域4的S4螺旋在激活和失活之间的偶联中起关键作用。
