Key result
The V876E HypoPP1 mutation generates a gating pore current that carries strong resting Na+ inward currents in physiological conditions compared to wild-type channels.
The V876E mutation in HypoPP1 generates a gating pore current carrying strong resting Na+ inward currents, likely responsible for severe paralysis symptoms.
Supports gating pore Na+ leak in HypoPP1 model; leaves open human therapeutic translation.
Type 1 hypokalemic periodic paralysis (HypoPP1) is a poorly understood genetic neuromuscular disease characterized by episodic attacks of paralysis associated with low blood K+. The vast majority of HypoPP1 mutations involve the replacement of an arginine by a neutral residue in one of the S4 segments of the α1 subunit of the skeletal muscle voltage-gated Ca2+ channel, which is thought to generate a pathogenic gating pore current. The V876E HypoPP1 mutation has the peculiarity of being located in the S3 segment of domain III, rather than an S4 segment, raising the question of whether such a mutation induces a gating pore current. Here we successfully transfer cDNAs encoding GFP-tagged human wild-type (WT) and V876E HypoPP1 mutant α1 subunits into mouse muscles by electroporation. The expression profile of these WT and V876E channels shows a regular striated pattern, indicative of their localization in the t-tubule membrane. In addition, L-type Ca2+ current properties are the same in V876E and WT fibers. However, in the presence of an external solution containing low-Cl− and lacking Na+ and K+, V876E fibers display an elevated leak current at negative voltages that is increased by external acidification to a higher extent in V876E fibers, suggesting that the leak current is carried by H+ ions. However, in the presence of Tyrode’s solution, the rate of change in intracellular pH produced by external acidification was not significantly different in V876E and WT fibers. Simultaneous measurement of intracellular Na+ and current in response to Na+ readmission in the external solution reveals a rate of Na+ influx associated with an inward current, which are both significantly larger in V876E fibers. These data suggest that the V876E mutation generates a gating pore current that carries strong resting Na+ inward currents in physiological conditions that are likely responsible for the severe HypoPP1 symptoms associated with this mutation.
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Fuster et al. (2017) studied Type 1 hypokalemic periodic paralysis (HypoPP1). V876E HypoPP1 mutant α1 subunit vs. Wild-type (WT) α1 subunit was evaluated on Na+ leak current and intracellular Na+ influx. The V876E HypoPP1 mutation generates a gating pore current that carries strong resting Na+ inward currents in physiological conditions compared to wild-type channels.
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