Depolarization-activated gating pore current conducted by mutant sodium channels in potassium-sensitive normokalemic periodic paralysis

Some inherited periodic paralyses are caused by mutations in skeletal muscle Na(v)1.4 sodium channels that alter channel gating and impair action potential generation. In the case of hypokalemic periodic paralysis, mutations of one of the outermost two gating charges in the S4 voltage sensor in domain II of the Na(v)1.4 alpha subunit induce gating pore current, resulting in a leak of sodium or protons through the voltage sensor that causes depolarization, sodium overload, and contractile failure correlated with low serum potassium. Potassium-sensitive normokalemic periodic paralysis (NormoPP) is caused by mutations in the third gating charge in domain II of the Na(v)1.4 channel. Here, we report that these mutations in rat Na(v)1.4 (R669Q/G/W) cause gating pore current that is activated by depolarization and therefore is conducted in the activated state of the voltage sensor. In addition, we find that this gating pore current is retained in the slow-inactivated state and is deactivated only at hyperpolarized membrane potentials. Gating pore current through the mutant voltage sensor of slow-inactivated NormoPP channels would cause increased sodium influx at the resting membrane potential and during trains of action potentials, depolarize muscle fibers, and lead to contractile failure and cellular pathology in NormoPP.