Human sodium channel gating defects caused by missense mutations in S6 segments associated with myotonia: S804F and V1293I
Human sodium channel gating defects caused by missense mutations in S6 segments associated with myotonia: S804F and V1293I
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DOI：
10.1111/j.1469-7793.1998.685bj.x
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发表时间：
1998-08-01
影响因子：
5.5
通讯作者：
Cannon, SC
中科院分区：
文献类型：
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作者：
Green, DS;George, AL;Cannon, SC
1.人骨骼肌钠通道α亚基（hSkM 1）的错义突变已在某些遗传性形式或肌强直中被检测到。通过记录Na+电流从细胞转染的cDNA编码野生型或突变hSkM 1，我们的特点是功能性后果的两个肌强直相关的突变，位于胞质末端的第六个跨膜段的结构域II（S804 F）或结构域III（V1293 I）。这两个突变引起适度的，但明确的，改变电压依赖性门控行为的hSkM 1。对于S804 F，异常仅限于快速失活：50 ms去极化结束时的持续Na+电流增加3倍，开放状态的失活速率减慢2倍，快速失活的电压依赖性（h（无穷大））偏移+3 mV。V1293 I也破坏了快速失活，在超极化电位（小于或等于-70 mV）下恢复速率快3倍。V1293 I的激活也发生了改变：电压依赖性偏移了-6 mV（超极化）。S804 F或V1293I.4不改变慢失活。我们认为S804 F和V1293 I不是良性多态性。任一突变导致通道门控的可检测改变，并且在模型模拟中，缺陷的幅度足以产生肌强直放电的运行。
1. Missense mutations in the alpha-subunit of the human skeletal muscle sodium channel (hSkM1) have been detected In some heritable forms or myotonia. By recording Na+ currents from cells transfected with cDNA encoding either wild-type or mutant hSkM1, we characterized the functional consequences of two myotonia-associated mutations that lie at the cytoplasmic end of the sixth transmembrane segment in domain II (S804F) or domain III (V1293I).2. Both mutations caused modest, but unequivocal, alterations in the voltage-dependent gating behaviour of hSkM1. For S804F, the abnormalities were limited to fast inactivation: the persistent Na+ cnrrent at the end of a 50 ms depolarization was increased 3-fold, the rate of inactivation from the open state was slowed 2-fold, and the voltage dependence of fast inactivation (h(infinity)) was shifted by +3 mV. V1293I also disrupted fast inactivation, as evidenced by a 3-fold faster rate of recovery at hyperpolarized potentials (less than or equal to -70 mV). Activation was altered as well for V1293I: the voltage dependence was shifted by -6 mV (hyperpolarized).3. Slow inactivation was not altered by S804F or V1293I.4. We conclude that S804F and V1293I are not benign polymorphisms. Either mutation causes detectable alterations in channel gating and, in model simulations, the magnitude of the defects is sufficient to produce runs of myotonic discharges.