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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Depolarization-activated Gating Pore Current Conducted By Mutant Sodium Channels In Potassium-sensitive Normokalemic Periodic Paralysis
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Depolarization-activated Gating Pore Current Conducted By Mutant Sodium Channels In Potassium-sensitive Normokalemic Periodic Paralysis

机译：钾敏感的非钾性周期性麻痹中突变钠通道传导的去极化激活门控孔电流。

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摘要

Some inherited periodic paralyses are caused by mutations in skeletal muscle Na_v1.4 sodium channels that alter channel gating and impair action potential generation. In the case of hypokalemic periodic paralysis, mutations of one of the outermost two gating charges in the S4 voltage sensor in domain II of the Na_v1.4 α subunit induce gating pore current, resulting in a leak of sodium or protons through the voltage sensor that causes depolarization, sodium overload, and contractile failure correlated with low serum potassium. Potassium-sensitive normokalemic periodic paralysis (NormoPP) is caused by mutations in the third gating charge in domain II of the Na_v1.4 channel. Here, we report that these mutations in rat Na_v1.4 (R669Q/G/W) cause gating pore current that is activated by depolarization and therefore is conducted in the activated state of the voltage sensor. In addition, we find that this gating pore current is retained in the slow-inactivated state and is deactivated only at hyperpolarized membrane potentials. Gating pore current through the mutant voltage sensor of slow-inactivated NormoPP channels would cause increased sodium influx at the resting membrane potential and during trains of action potentials, depolarize muscle fibers, and lead to contractile failure and cellular pathology in NormoPP.
机译：一些遗传性周期性麻痹是由骨骼肌Na_v1.4钠通道的突变引起的，这些突变会改变通道门控并削弱动作电位的产生。在低钾性周期性麻痹的情况下，Na_v1.4α亚基域II的S4电压传感器中最外面的两个门控电荷之一的突变会诱发门控孔隙电流，从而导致钠或质子通过电压传感器泄漏，引起去极化，钠超载和收缩衰竭，与血清钾水平低有关。钾敏感的常钾性周期性麻痹（NormoPP）是由Na_v1.4通道的结构域II中的第三个门控电荷的突变引起的。在这里，我们报道大鼠Na_v1.4（R669Q / G / W）中的这些突变会导致门控孔电流，该电流被去极化激活，因此在电压传感器的激活状态下进行。此外，我们发现该选通孔电流保持在慢速灭活状态，仅在超极化膜电势下才失活。通过慢速灭活的NormoPP通道的突变型电压传感器选通的孔电流会导致静息膜电位和一系列动作电位期间钠流入增加，使肌纤维去极化，并导致NormoPP的收缩衰竭和细胞病变。

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