A calcium channel mutant mouse model of hypokalemic periodic paralysis

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 _V1.1) or a sodium channel (Na_V1.4) accounting for 60% and 20% of cases, respectively. The mechanistic link between Ca_V1.1 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_V1.1 R528H mutation. The Ca_v1.1 R528H mice had a HypoPP phenotype for which low K⁺ challenge produced a paradoxical depolarization of 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 _V1.1 R528H mouse had a small anomalous inward current at the resting potential, similar to our observations in the Na_V1.4 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.