Altered Fast And Slow Inactivation Of The N440k Na(V)1.4 Mutant In A Periodic Paralysis Syndrome

Objective: To electrophysiologically characterize the Na(v)1.4 mutant N440K found in a Korean family with a syndrome combining symptoms of paramyotonia congenita, hyperkalemic periodic paralysis, and potassium-aggravated myotonia.Methods: We characterized transiently expressed wild-type and mutant Na(v)1.4 using whole-cell voltage-clamp analysis.Results: N440K produced a significant depolarizing shift in the voltage dependence of fast inactivation and increased persistent current and acceleration in fast inactivation recovery, which gave rise to a 2-fold elevation in the dynamic availability of the mutant channels. In addition, the mutant channels required substantially longer and stronger depolarization to enter the slow-inactivated state.Conclusions: N440K causes a gain of function consistent with skeletal muscle hyperexcitability as observed in individuals with the mutation. How the same mutation results in distinct phenotypes in the 2 kindreds remains to be determined. Neurology (R) 2012;79:1033-1040