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Gating pore current in an inherited ion channelopathy

机译：遗传性离子通道病的门控孔电流

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Ion channelopathies are inherited diseases in which alterations in control of ion conductance through the central pore of ion channels impair cell function, leading to periodic paralysis, cardiac arrhythmia, renal failure, epilepsy, migraine and ataxia. Here we show that, in contrast with this well-established paradigm, three mutations in gating-charge-carrying arginine residues in an S4 segment that cause hypokalaemic periodic paralysis induce a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle Na_V1.4 channel. This 'gating pore current' is active at the resting membrane potential and closed by depolarizations that activate the voltage sensor. It has similar permeability to Na~+, K~+ and Cs~+, but the organic monovalent cations tetraethylammonium and N-methyl-D-glucamine are much less permeant. The inorganic divalent cations Ba~(2+), Ca~(2+) and Zn~(2+) are not detectably permeant and block the gating pore at millimolar concentrations. Our results reveal gating pore current in naturally occurring disease mutations of an ion channel and show a clear correlation between mutations that cause gating pore current and hypokalaemic periodic paralysis. This gain-of-function gating pore current would contribute in an important way to the dominantly inherited membrane depolarization, action potential failure, flaccid paralysis and cytopathology that are characteristic of hypokalaemic periodic paralysis. A survey of other ion channelopathies reveals numerous examples of mutations that would be expected to cause gating pore current, raising the possibility of a broader impact of gating pore current in ion channelopathies.
机译：离子通道病是遗传性疾病，其中通过离子通道中心孔的离子电导控制改变会损害细胞功能，导致周期性麻痹，心律不齐，肾衰竭，癫痫，偏头痛和共济失调。在这里，我们表明，与这种公认的范式相反，S4段中携带选通电荷的精氨酸残基的三个突变引起低钾血症性周期性麻痹，通过骨骼肌Na_V1的电压传感器诱导超极化激活的阳离子泄漏。 4通道。这种“门控孔隙电流”在静止的膜电位上起作用，并被激活电压传感器的去极化作用所封闭。它具有类似于Na〜+，K〜+和Cs〜+的磁导率，但是有机一价阳离子四乙铵和N-甲基-D-葡糖胺的渗透性低得多。无机二价阳离子Ba〜（2 +），Ca〜（2+）和Zn〜（2+）不可检测地渗透，并在毫摩尔浓度下堵塞门控孔。我们的研究结果揭示了自然发生的离子通道疾病突变中的门控孔电流，并显示了导致门控孔电流的突变与低钾血症性周期性麻痹之间的明确相关性。这种功能获得的门控孔电流将以重要的方式促进低钾血症性周期性麻痹的特征性遗传性膜去极化，动作电位衰竭，松弛性麻痹和细胞病理学。对其他离子通道病的调查揭示了许多有望导致选通孔电流的突变实例，从而增加了门孔电流在离子通道病中产生更广泛影响的可能性。

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