Gating pore current in an inherited ion channelopathy
Gating pore current in an inherited ion channelopathy
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DOI：
10.1038/nature05598
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发表时间：
2007-03-01
期刊：
影响因子：
64.8
通讯作者：
Catterall, William A.
中科院分区：
文献类型：
--
作者：
Sokolov, Stanislav;Scheuer, Todd;Catterall, William A.
离子通道病是一种遗传性疾病，其中通过离子通道中心孔的离子电导控制的改变损害细胞功能，导致周期性麻痹、心律失常、肾衰竭、癫痫、偏头痛和共济失调（1）。在这里，我们表明，与这种成熟的范例相反，S4段中携带门控电荷的精氨酸残基的三个突变导致低钾型周期性麻痹（2），通过骨骼肌Na（V）1.4通道的电压传感器诱导超极化激活的阳离子泄漏。这种“门控孔电流”在静息膜电位下是活跃的，并通过激活电压传感器的去极化而关闭。它对Na+、K+和Cs+具有类似的渗透性，但有机单价阳离子四乙基铵和N-甲基-D-葡糖胺的渗透性要小得多。无机二价阳离子Ba 2+、Ca 2+和Zn 2+不可检测地渗透，并且在毫摩尔浓度下阻塞门控孔。我们的研究结果揭示了门控孔电流在自然发生的疾病突变的离子通道，并显示了明确的相关性突变，导致门控孔电流和低钾型周期性麻痹。这种功能获得性门控孔电流将以一种重要的方式促成显性遗传的膜去极化、动作电位衰竭、弛缓性麻痹和细胞病理学，这些都是低钾性周期性麻痹的特征。对其他离子通道病的调查揭示了许多预期会引起门控孔电流的突变的例子，提高了门控孔电流在离子通道病中产生更广泛影响的可能性。
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(1). 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(2) induce a hyperpolarization- activated cationic leak through the voltage sensor of the skeletal muscle Na(V)1.4 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 Ba2+, Ca2+ and Zn2+ 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.