Abstract
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.
Highlights
The phenotypic expression of most muscle channelopathies takes place within the first two decades of life, and many afflicted individuals suffer from life-long symptoms such as muscle stiffness, weakness, or pain[9]
Newer studies described a cation leak with characteristics similar to the ω-current in Shaker potassium channels. These findings indicate a form of gain-of-function resulting in periodic paralysis[15,16,17,18]
In the sliding-helix model of voltage-sensor movement during activation, when the potential across the cell membrane becomes depolarized, the voltage-sensor domain (VSD) undergoes an outward movement. This movement pulls on the S4-S5 linker and drags open the pore-domain (PD), leading to an influx of sodium ions[33]. Based on this model we sought to determine whether P1158S alters the S4-S5 topology
Summary
The phenotypic expression of most muscle channelopathies takes place within the first two decades of life, and many afflicted individuals suffer from life-long symptoms such as muscle stiffness, weakness, or pain[9]. There is an increase in muscle membrane excitability in which even a brief voluntary contraction can lead to a series of action potentials that can persist for several seconds following the termination of motor neuron activity. This phenomenon is perceived as muscle stiffness[9]. Newer studies described a cation leak with characteristics similar to the ω-current in Shaker potassium channels These findings indicate a form of gain-of-function resulting in periodic paralysis[15,16,17,18]. Some channelopathies are triggered by low serum potassium levels and manifest in episodes of extreme muscle weakness These are known as hypo-kalemic periodic paralyses (hypoPP)[19]. We hypothesized that pH alterations may push P1158S towards either myotonia or hypoPP
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