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

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Abstract
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 under- lying 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+ equilib- rium potential. It also is well established that voltage- gated K+ channels can conduct or transport protons when specifi c 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 that a mutation in the voltage sensing domain of a voltage-gated Na+ chan- nel can behave similarly and further raise the question of whether this additional membrane conductance for protons may be relevant for the pathogenesis of the dis- ease (hypokalemic periodic paralysis). Superfamily of Voltage-gated Cation Channels Voltage-gated cation channels (VCCs) are proteins that conduct Na+, Ca2+, or K+ with high selectivity through a central, so-called α pore. Precise control of channel opening and closing is necessary for proper cell excit- ability and particularly the generation of action poten- tials. VCC are characterized by at least one ion-conducting open and two nonconducting states, one from which the channel can be activated (the resting state) and one from which it cannot (the inactivated state). The transi- tion from one state to another is voltage dependent. The function of the channels' voltage-sensing domains has been extensively characterized. Generally, VCCs consist of four repeats (I-IV) of domains, consisting of six transmembrane α-helical seg- ments, S1-S6. The voltage-sensing domain is formed by S1-S4 with S4 being the most mobile region—thought to move outward along a helical screw (for review see Lehmann-Horn and Jurkat-Rott, 1999). Because S4 car- ries a positive amino acid residue at every third position, the S4 movement through the electric fi eld of the mem- brane generates the so-called gating current even when the α pore is blocked. The depolarization-driven out- ward movement of S4 drives the conformational change that results in channel activation and conduction of ions through the central α pore formed by S5 and S6 and the intervening linker. Hyperpolarization-activated Cation Currents through Mutant VCC