A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH-Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels
2018
Skeletal muscle
channelopathies, many of which are inherited as autosomal dominant mutations, include
myotoniaand
periodic paralysis.
Myotoniais defined by a delayed relaxation after muscular contraction, whereas
periodic paralysisis 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-
S5linker of the “skeletal muscle”,
Nav1.4, has been implicated in causing both
myotoniaand hypoPP. A common trigger for these conditions is physical activity. We previously reported that
Nav1.4is 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
Nav1.4into a proton-sensitive
channel.
Usingaction 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.
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