Do Hyperpolarization-induced Proton Currents Contribute to the Pathogenesis of Hypokalemic Periodic Paralysis, a Voltage Sensor Channelopathy?

An increasing number of human diseases have been found to result from mutations in ion channels, including voltage-gated cation channels. Though the mutations are known, the pathophysiological mechanisms underlying many of these channelopathies remain unclear. In this issue of the Journal, Struyk and Cannon (see p. 11) provide evidence for a novel mechanism, proton movement catalyzed by the voltage-sensing domain of the mutant channels. It already is known that voltage-gated proton channels resemble the voltage sensor domains of cation channels and show depolarization-induced outward currents and current reversal at the H⁺ equilibrium potential. It also is well established that voltage-gated K⁺ channels can conduct or transport protons when specific voltage sensor arginines are replaced by histidines—and that the pathway for the protons differs from the K⁺ conducting pore (Starace et al., 1997). In this issue, Struyk and Cannon show...