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NaV1.4 mutations cause hypokalaemic periodic paralysis by disrupting IIIS4 movement during recovery.
NaV1.4 突变通过在恢复过程中中断 IIIS4 运动引起低钾性周期性瘫痪。
hypokalaemic periodic paralysis molecular dynamics omega pore current sodium channel voltage sensor
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摘要

Hypokalaemic periodic paralysis is typically associated with mutations of voltage sensor residues in calcium or sodium channels of skeletal muscle. To date, causative sodium channel mutations have been studied only for the two outermost arginine residues in S4 voltage sensor segments of domains I to III. These mutations produce depolarization of skeletal muscle fibres in response to reduced extracellular potassium, owing to an inward cation-selective gating pore current activated by hyperpolarization. Here, we describe mutations of the third arginine, R3, in the domain III voltage sensor i.e. an R1135H mutation which was found in two patients in separate families and a novel R1135C mutation identified in a third patient in another family. Muscle fibres from a patient harbouring the R1135H mutation showed increased depolarization tendency at normal and reduced extracellular potassium compatible with the diagnosis. Additionally, amplitude and rise time of action potentials were reduced compared with controls, even for holding potentials at which all NaV1.4 are fully recovered from inactivation. These findings may be because of an outward omega current activated at positive potentials. Expression of R1135H/C in mammalian cells indicates further gating defects that include significantly enhanced entry into inactivation and prolonged recovery that may additionally contribute to action potential inhibition at the physiological resting potential. After S4 immobilization in the outward position, mutant channels produce an inward omega current that most likely depolarizes the resting potential and produces the hypokalaemia-induced weakness. Gating current recordings reveal that mutations at R3 inhibit S4 deactivation before recovery, and molecular dynamics simulations suggest that this defect is caused by disrupted interactions of domain III S2 countercharges with S4 arginines R2 to R4 during repolarization of the membrane. This work reveals a novel mechanism of disrupted S4 translocation for hypokalaemic periodic paralysis mutations at arginine residues located below the gating pore constriction of the voltage sensor module. 

译文

低钾性周期性麻痹通常与骨骼肌钙或钠通道中电压传感器残基的突变有关。迄今为止,仅研究了结构域 I 至 III 的 S4 电压传感器段中的两个最外层精氨酸残基的致病钠通道突变。由于超极化激活的向内阳离子选择性门控孔电流,这些突变对细胞外钾减少的反应产生骨骼肌纤维去极化。在这里,我们描述了第三精氨酸 R3 的突变, 在域 III 电压传感器中,即在不同家族的两个患者中发现了 R1135H 突变,在另一个家族的第三个患者中发现了新的 R1135C 突变。来自携带 R1135H 突变的患者的肌肉纤维在正常情况下表现出增加的去极化趋势,并且与诊断相符的细胞外钾减少。此外,与对照组相比,动作电位的幅度和上升时间降低了,即使对于所有 NaV1.4 从失活中完全恢复的保持电位也是如此。这些发现可能是因为在正电位时激活了向外的 omega 电流。哺乳动物细胞中 R1135H/C 的表达表明进一步的门控缺陷,包括显著增强进入失活和延长恢复,这可能另外有助于生理静息电位的动作电位抑制。S4 在外向位置固定后,突变通道产生向内的 omega 电流,该电流最有可能使静息电位去极化,并产生低钾血症引起的无力。门控电流记录显示 R3 的突变在恢复前抑制 S4 失活, 分子动力学模拟表明,这种缺陷是由结构域 III S2 与 S4 精氨酸 R2 到 R4 在膜复极期间的抵消作用中断造成的。这项工作揭示了一种新的机制,这种机制破坏了位于电压传感器模块门控孔收缩下方的精氨酸残基的低钾周期性瘫痪突变的 S4 易位。

Periodic Paralysis

神经 瘫痪 疾病
概述  :  

 周期性瘫痪是以周期性反复发作的骨骼肌短暂性弛缓性瘫痪为特征的一组疾病。按发病时的血清钾浓度和症状可分为低血钾型、高血钾型和正常血钾型三型,其中以低血钾型最多见。 病因 本病的病因及发病机理迄今尚未阐明。除甲状腺、肾上腺等内分泌机能失调可为本病的原因外,许多对糖代谢,水与电解质平衡有影响的情况也可引起类似周期性瘫痪的发作。钾盐不仅与电解质平衡及糖的中间代谢过程有关,而且对正常的神经传导及神经肌肉接头点的应激能有密切关系。肌肉瘫痪的发生似与患者血清钾离子浓度的改变

periodic    英 [,pɪərɪ'ɒdɪk]  美 [,pɪrɪ'ɑdɪk] 

释    义    adj. 周期的;定期的

同根词    period adj. 某一时代的 periodical [数] 周期的;定期的

periodically adv. 定期地;周期性地;偶尔;间歇

period n. 周期,期间;时期;月经;课时 

periodical n. 期刊;杂志 periodicity [数] 周期性;频率;定期性

例    句   The periodic movements of the universe are the same, up and down from age to age.  宇宙的周期运动是同样的,从一个时代到另一个时代往返不已。

 

paralysis  英 [pə'rælɪsɪs]  美 [pə'ræləsɪs] 

释    义    n. 麻痹;无力;停顿

同根词    paralyzed adj. 瘫痪的;麻痹的 

paralytic adj. 麻痹的;瘫痪的;中风的

paralytic n. 中风患者;麻痹患者

paralyzed v. 使麻痹;使无力;使失去勇气

paralyze vt. 使麻痹;使瘫痪 

paralyse vt. 使……无力;使……麻痹;使……瘫痪

例    句   An emotional person, mind, and no paralysis. 一个有情感的人,心,不再麻痹。

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