Elevated resting H+ current in the R1239H type 1 hypokalaemic periodic paralysis mutated Ca2+ channel
Elevated resting H+ current in the R1239H type 1 hypokalaemic periodic paralysis mutated Ca2+ channel
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DOI：
10.1113/jp274638
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发表时间：
2017-10-15
影响因子：
5.5
通讯作者：
Allard, Bruno
中科院分区：
文献类型：
--
作者：
Fuster, Clarisse;Perrot, Jimmy;Allard, Bruno
编码骨骼肌电压门控钙通道α 1亚基的基因的错义突变可诱导1型低钾血症性周期性麻痹，这是一种了解较少的神经肌肉疾病，其特征为与低血清K+相关的间歇性麻痹发作。本研究的目的是确定急性表达的R1239H低钾型周期性麻痹的人突变体α 1亚基的钙离子通道在成熟的肌肉环境中诱导的肌纤维电特性的变化，以更好地了解这种疾病的病理生理机制。我们将编码野生型和R1239H突变体人Ca2+通道的基因转移到后肢小鼠肌肉中，通过电穿孔和结合电压钳和细胞内pH测量酶促解离的单肌纤维。与表达野生型α 1亚基的纤维相比，表达R1239H突变体的纤维显示出幅度降低的Ca2+电流和较高的静息泄漏内向电流，该电流通过外部酸化而增加。外部酸化也产生细胞内酸化在R1239H纤维，并抑制内向整流K+电流以更高的速率。这些数据表明，R1239H突变诱导一个升高的泄漏H+电流在休息时流过一个门控孔创建的突变和外部酸化有利于肌肉麻痹的发病，通过增强H+去极化电流和抑制静息内向整流K+电流。因此，我们的研究结果可以解释为什么麻痹发作优先发生在剧烈肌肉锻炼后的恢复期。
Missense mutations in the gene encoding the alpha 1 subunit of the skeletal muscle voltage-gated Ca2+ channel induce type 1 hypokalaemic periodic paralysis, a poorly understood neuromuscular disease characterized by episodic attacks of paralysis associated with low serum K+. The present study aimed at identifying the changes in muscle fibre electrical properties induced by acute expression of the R1239H hypokalaemic periodic paralysis human mutant alpha 1 subunit of Ca2+ channels in a mature muscle environment to better understand the pathophysiological mechanisms involved in this disorder. We transferred genes encoding wild-type and R1239H mutant human Ca2+ channels into hindlimb mouse muscle by electroporation and combined voltage-clamp and intracellular pH measurements on enzymatically dissociated single muscle fibres. As compared to fibres expressing wild-type alpha 1 subunits, R1239H mutant-expressing fibres displayed Ca2+ currents of reduced amplitude and a higher resting leak inward current that was increased by external acidification. External acidification also produced intracellular acidification at a higher rate in R1239H fibres and inhibited inward rectifier K+ currents. These data indicate that the R1239H mutation induces an elevated leak H+ current at rest flowing through a gating pore created by the mutation and that external acidification favours onset of muscle paralysis by potentiating H+ depolarizing currents and inhibiting resting inward rectifier K+ currents. Our results could thus explain why paralytic attacks preferentially occur during the recovery period following intense muscle exercise.