NaV1.4 mutations cause hypokalaemic periodic paralysis by disrupting IIIS4 movement during recovery.
NaV1.4 mutations cause hypokalaemic periodic paralysis by disrupting IIIS4 movement during recovery.
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DOI：
10.1093/brain/awu015
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Jurkat-Rott K
中科院分区：
文献类型：
--
作者：
Groome JR;Lehmann-Horn F;Fan C;Wolf M;Winston V;Merlini L;Jurkat-Rott K
通过突变的钠或钙通道的电压传感器泄漏的阳离子是低血钾性周期性麻痹的基础。Groome等人。使用肌肉纤维记录、电压钳和分子动力学来研究最近发现的Nav1.4通道突变。他们发现了一种新的电压传感器运动，可以解释肌肉病理。低血钾性周期性麻痹通常与骨骼肌钙或钠通道中电压感受器残基的突变有关。到目前为止，导致钠通道突变的研究只针对结构域I到III的S4电压传感器片段中最外面的两个精氨酸残基。由于超极化激活的内向阳离子选择性门控孔电流，这些突变导致骨骼肌纤维对细胞外钾的减少做出去极化反应。在这里，我们描述了结构域III电压传感器中第三个精氨酸R3的突变，即在不同家系的两名患者中发现的R1135H突变和在另一家系的第三名患者中发现的一种新的R1135C突变。一名携带R1135H突变的患者的肌肉纤维在正常情况下表现出更强的去极化倾向，并与诊断相一致的细胞外钾减少。此外，与对照组相比，动作电位的幅度和上升时间减小，即使在所有NAV1.4完全从失活状态恢复的保持电位下也是如此。这些发现可能是因为外向欧米伽电流在正电位下被激活。在哺乳动物细胞中R1135H/C的表达表明存在进一步的门控缺陷，包括显著增强进入失活状态和延长恢复时间，这可能还有助于生理静息电位的动作电位抑制。在S4固定在外向位置后，突变通道产生内向omega电流，该电流很可能使静息电位去极化，并产生低钾血症引起的虚弱。门控电流记录显示，R3处的突变抑制了S4在恢复之前的失活，分子动力学模拟表明，这一缺陷是由于在膜的复极化过程中，结构域III S2的反电荷与S4精氨酸R2至R4的相互作用中断所致。这项工作揭示了电压传感器模块门孔狭窄下方精氨酸残基突变的低钾性周期性麻痹突变的S4错位的新机制。
Cations leaking through the voltage sensor of mutant sodium or calcium channels underlie hypokalaemic periodic paralysis. Groome et al. use muscle fibre recordings, voltage clamp, and molecular dynamics, to investigate recently discovered Nav1.4 channel mutations. They identify a novel voltage sensor movement that may explain the muscle pathology. 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.
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影响因子：
9.9
作者：
Matthews, E.;Labrum, R.;Hanna, M. G.
通讯作者：
Hanna, M. G.
影响因子：
3.4
作者：
RUDEL, R;LEHMANNHORN, F;KUTHER, G
通讯作者：
KUTHER, G
影响因子：
3.1
作者：
Sung, Chih-Chien;Cheng, Chih-Jen;Lin, Shih-Hua
通讯作者：
Lin, Shih-Hua
DOI：
10.1085/jgp.201210935
发表时间：
2013-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
Groome JR;Winston V
通讯作者：
Winston V
DOI：
10.1085/jgp.200709755
发表时间：
2007-07
期刊：
The Journal of general physiology
影响因子：
--
作者：
Struyk AF;Cannon SC
通讯作者：
Cannon SC