A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton-selective gating pore.
A Na+ channel mutation linked to hypokalemic periodic paralysis exposes a proton-selective gating pore.
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DOI：
10.1085/jgp.200709755
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发表时间：
2007-07
期刊：
影响因子：
--
通讯作者：
Cannon SC
中科院分区：
文献类型：
--
作者：
Struyk AF;Cannon SC
遗传性肌肉疾病低钾型周期性麻痹（HypoPP）的特征是由持续的肌膜去极化引起的弛缓性无力发作。HypoPP与CaV1.1（骨骼肌L型Ca2+通道）或NaV1.4（骨骼肌电压门控Na+通道）的S4电压敏感段中带电残基的错义突变存在遗传联系。虽然这些突变改变了两个通道的门控，但这些功能缺陷已被证明不足以解释受影响肌肉的肌膜去极化。最近对S4电压敏感结构域的拓扑结构的了解引起了人们对另一种病理机制的兴趣，其中HypoPP突变可能通过解除S4片段所在的假定水裂隙（“门控孔”）的阻塞而产生异常的离子漏导。我们测试了在结构域II中S4的最外精氨酸处具有HypoPP突变R663H（人R669H直系同源物）的NaV1.4的大鼠同种型的门控孔电导。我们发现，突变R663 H允许质子的跨膜渗透，但不允许更大的阳离子，类似于Shaker K+通道S4位点处组氨酸取代所显示的电导。这些结果与以下概念一致：当电压传感器向内定位时，DIIS4区段中的最外带电残基同时可接近细胞质和细胞外空间。相对于静息K+和Cl−电导，成熟骨骼肌中质子泄漏的预测幅度很小，因此不太可能完全解释麻痹发作背后的异常肌膜去极化。相反，持续的质子泄漏可能间接导致VREST的不稳定，例如，通过干扰细胞内pH稳态。
The heritable muscle disorder hypokalemic periodic paralysis (HypoPP) is characterized by attacks of flaccid weakness, brought on by sustained sarcolemmal depolarization. HypoPP is genetically linked to missense mutations at charged residues in the S4 voltage-sensing segments of either CaV1.1 (the skeletal muscle L-type Ca2+ channel) or NaV1.4 (the skeletal muscle voltage-gated Na+ channel). Although these mutations alter the gating of both channels, these functional defects have proven insufficient to explain the sarcolemmal depolarization in affected muscle. Recent insight into the topology of the S4 voltage-sensing domain has aroused interest in an alternative pathomechanism, wherein HypoPP mutations might generate an aberrant ionic leak conductance by unblocking the putative aqueous crevice (“gating-pore”) in which the S4 segment resides. We tested the rat isoform of NaV1.4 harboring the HypoPP mutation R663H (human R669H ortholog) at the outermost arginine of S4 in domain II for a gating-pore conductance. We found that the mutation R663H permits transmembrane permeation of protons, but not larger cations, similar to the conductance displayed by histidine substitution at Shaker K+ channel S4 sites. These results are consistent with the notion that the outermost charged residue in the DIIS4 segment is simultaneously accessible to the cytoplasmic and extracellular spaces when the voltage sensor is positioned inwardly. The predicted magnitude of this proton leak in mature skeletal muscle is small relative to the resting K+ and Cl− conductances, and is thus not likely to fully account for the aberrant sarcolemmal depolarization underlying the paralytic attacks. Rather, it is possible that a sustained proton leak may contribute to instability of VREST indirectly, for instance, by interfering with intracellular pH homeostasis.
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影响因子：
9.9
作者：
Bulman, DE;Scoggan, KA;Ebers, GC
通讯作者：
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DOI：
10.1016/j.bbrc.2006.07.101
发表时间：
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