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(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 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(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.
Pubmed ID: 23187123 RIS Download
Action Potentials | Analysis of Variance | Animals | Calcium Channels, L-Type | Disease Models, Animal | Electric Stimulation | Excitation Contraction Coupling | Female | Glucose | Humans | Hypokalemic Periodic Paralysis | In Vitro Techniques | Insulin | Lysosomal Storage Diseases | Male | Mice | Mice, 129 Strain | Muscle Contraction | Muscle Fibers, Skeletal | Muscle Weakness | Muscle, Skeletal | Muscular Diseases | Mutation, Missense | Phenotype