Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis
Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis
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DOI：
10.1016/j.bbrc.2006.07.101
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发表时间：
2006-09-22
影响因子：
3.1
通讯作者：
Tabti, Nacira
中科院分区：
文献类型：
--
作者：
Carle, Thomas;Lhuillier, Loic;Tabti, Nacira
低钾性周期性麻痹2型（hypoPP2）是一种遗传性骨骼肌疾病，由编码骨骼肌Na+通道α亚基的SCN4A基因错义突变引起（Nav1.4）。迄今为止报道的所有hypoPP2突变都针对II结构域（R672/G/H/S）的电压传感器S4的精氨酸残基。我们发现了一个新的hypoPP2突变，该突变可以中和DIII-S4 （R1132Q）中的精氨酸残基，并研究了其在转染人SCN4A cDNA的HEK细胞中的功能后果。全细胞电流记录显示快速和慢速失活的增强，以及激活曲线的去极化移位。在r1132q和R672S突变体中，单一Na+电导保持正常，因此不能解释hypoPP2中Na+电流的减少。总之，我们的研究结果为r1132在通道激活和失活中的作用提供了明确的证据，并证实了hypoPP2突变导致肌肉低兴奋性的功能丧失效应。(c) 2006爱思唯尔公司版权所有。
Hypokalemic periodic paralysis type 2 (hypoPP2) is an inherited skeletal muscle disorder caused by missense mutations in the SCN4A gene encoding the alpha subunit of the skeletal muscle Na+ channel (Nav1.4). All hypoPP2 mutations reported so far target an arginine residue of the voltage sensor S4 of domain II (R672/G/H/S). We identified a novel hypoPP2 mutation that neutralizes an arginine residue in DIII-S4 (R1132Q) and studied its functional consequences in HEK cells transfected with the human SCN4A cDNA. Whole-cell current recordings revealed an enhancement of both fast and slow inactivation, as well as a depolarizing shift of the activation curve. The unitary Na+ conductance remained normal in R 1132Q and in R672S mutants, and cannot therefore account for the reduction of Na+ current presumed in hypoPP2. Altogether, our results provide a clear evidence for the role of R 1132 in channel activation and inactivation, and confirm loss of function effects of hypoPP2 mutations leading to muscle hypoexcitability. (c) 2006 Elsevier Inc. All rights reserved.