A calcium channel mutant mouse model of hypokalemic periodic paralysis

作者：Wu Fenfen; Mi Wentao; Hernandez Ochoa Erick O; Burns Dennis K; Fu Yu; Gray Hillery F; Struyk Arie F; Schneider Martin F; Cannon Stephen C^*

来源：Journal of Clinical Investigation, 2012, 122(12): 4580-4591.

DOI：10.1172/JCI66091

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.

• 出版日期2012-12