Mixed Periodic Paralysis & Myotonia Mutant Imparts pH Sensitivity in NaV1.4

Abstract

Skeletal muscle channelopathies, the majority of which are inherited as autosomal dominant mutations, are classified as either myotonia or periodic paralysis. Myotonias are defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis is associated with low potassium levels; hence it is known as hypokalemic periodic paralysis (hypoPP). Interestingly, the P1158S missense mutant located in the S4-S5 linker of the third domain of the “skeletal muscle” voltage-gated sodium channel, NaV1.4, has been implicated in causing both myotonia and hypoPP. A common trigger for these conditions is physical activity. Given that intense exercise is often accompanied by blood acidosis, we decided to determine whether changes in pH would push the P1158S towards either phenotype. We previously reported that NaV1.4 is relatively insensitive to changes in extracellular pH compared to NaV1.2 and NaV1.5. The results of our experiments with P1158S indicate that the voltage-dependence of activation and steady-state fast inactivation are hyperpolarized as pH increases, and persistent currents are increased at lower pH. Thus, P1185S turns the normally pH-insensitive NaV1.4 into a proton-sensitive channel.