Key result
The P1158S mutation turns the normally pH-insensitive Nav1.4 skeletal muscle sodium channel into a proton-sensitive channel, providing a mechanism for exercise-induced myotonia and periodic paralysis.
p-value: p=0.0011
The P1158S mutation makes the skeletal muscle sodium channel Nav1.4 sensitive to extracellular pH changes, providing a mechanistic link between exercise-induced acidosis and the dual phenotype of myotonia and periodic paralysis.
Suggests acidosis as trigger in myotonia/paralysis models; leaves open human validation and therapeutic targeting.
Skeletal muscle channelopathies, many of which are inherited as autosomal dominant mutations, include myotonia and periodic paralysis. Myotonia is defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis, known as hypokalemic periodic paralysis (hypoPP), is associated with low potassium levels. Interestingly, the P1158S missense mutant, located in the third domain S4-S5 linker of the "skeletal muscle", Nav1.4, has been implicated in causing both myotonia and hypoPP. A common trigger for these conditions is physical activity. We previously reported that Nav1.4 is relatively insensitive to changes in extracellular pH compared to Nav1.2 and Nav1.5. Given that intense exercise is often accompanied by blood acidosis, we decided to test whether changes in pH would push gating in P1158S towards either phenotype. Our results suggest that, unlike in WT-Nav1.4, low pH depolarizes the voltage-dependence of activation and steady-state fast inactivation, decreases current density, and increases late currents in P1185S. Thus, P1185S turns the normally pH-insensitive Nav1.4 into a proton-sensitive channel. Using action potential modeling we predict a pH-to-phenotype correlation in patients with P1158S. We conclude that activities which alter blood pH may trigger the noted phenotypes in P1158S patients.
No takes yet. Share an insight, caveat, or question.
Ghovanloo et al. (2018) studied Skeletal muscle channelopathies (myotonia and hypokalemic periodic paralysis). P1158S mutation in Nav1.4 vs. Wild-type Nav1.4 was evaluated on pH-sensitivity of channel gating (voltage-dependence of activation and steady-state fast inactivation) (p=0.0011). The P1158S mutation turns the normally pH-insensitive Nav1.4 skeletal muscle sodium channel into a proton-sensitive channel, providing a mechanism for exercise-induced myotonia and periodic paralysis.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: