The CaV1.1 R528H mutation in mice caused a hypokalemic periodic paralysis phenotype with paradoxical depolarization, loss of muscle excitability, and weakness during low potassium challenge due to an anomalous gating pore current.
The CaV1.1 R528H mouse model reveals that an anomalous gating pore current causes paradoxical depolarization and weakness in 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.
Wu et al. (Mon,) conducted a other in Hypokalemic periodic paralysis. CaV1.1 R528H mutation vs. Wild-type mice was evaluated on Muscle force and excitability during low K+ challenge. The CaV1.1 R528H mutation in mice caused a hypokalemic periodic paralysis phenotype with paradoxical depolarization, loss of muscle excitability, and weakness during low potassium challenge due to an anomalous gating pore current.
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