A calcium channel mutant mouse model of hypokalemic periodic paralysis
A calcium channel mutant mouse model of hypokalemic periodic paralysis
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DOI：
10.1172/jci66091
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发表时间：
2012-12-01
影响因子：
15.9
通讯作者：
Cannon, Stephen C.
中科院分区：
文献类型：
--
作者：
Wu, Fenfen;Mi, Wentao;Cannon, Stephen C.
低血钾性周期性麻痹(HypoPP)是一种家族性骨骼肌疾病，表现为反复发作的严重无力，持续数小时至数天，与血钾(K+)降低相关。HypoPP具有遗传异质性，钙通道(Ca(V)1.1)和钠通道(Na(V)1.4)的错义突变分别占60%和20%。钙(V)1.1突变和肌肉兴奋性丧失之间的机制联系尚不清楚。为了解决这个问题，我们建立了一个带有靶向Ca(V)1.1R528H突变的HypoPP小鼠模型：Ca(V)1.1R528H小鼠具有HypoPP表型，低K+攻击导致静息电位的矛盾去极化、肌肉兴奋性丧失和虚弱。伴有横管扩张和三联体连接断裂的空泡性肌病损害了钙离子的释放，可能是轻度永久性无力的原因之一。与我们在Na(V)1.4R669H HypoPP小鼠模型中所观察到的相似，Ca(V)1.1R528H小鼠的纤维在静息电位有一个小的异常内向电流。这种“门控孔电流”可能是钙或钠通道S4电压传感器错义突变引起的反常去极化和对HypoPP易感性的常见机制。
Hypokalemic periodic paralysis (HypoPP) is a familial skeletal muscle disorder that presents with recurrent episodes of severe weakness lasting hours to days associated with reduced serum potassium (K+) HypoPP is genetically heterogeneous, with missense mutations of a calcium channel (Ca(V)1.1) or a sodium channel (Na(V)1.4) accounting for 60% and 20% of cases, respectively. The mechanistic link between Ca(v)1.1 mutations and the ictal loss of muscle excitability during an attack of weakness in HypoPP is unknown. To address this question, we developed a mouse model for HypoPP with a targeted Ca(V)1.1 R528H mutation: The Ca(v)1.1 R528H mice had a HypoPP phenotype for which low K+ challenge produced a paradoxical depolarization the resting potential, loss of muscle excitability, and weakness. A vacuolar myopathy with dilated transverse tubules and disruption of the triad junctions impaired Ca2+ release and likely contributed to the mild permanent weakness. Fibers from the Ca(V)1.1 R528H mouse had a small anomalous inward current at the resting potential, similar to our observations in the Na(V)1.4 R669H HypoPP mouse model. This "gating pore current" may be a common mechanism for paradoxical depolarization and susceptibility to HypoPP arising from missense Mutations in the S4 voltage sensor of either calcium or sodium channels.