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Gating pore current in an inherited ion channelopathy

Abstract

Ion channelopathies are inherited diseases in which alterations in control of ion conductance through the central pore of ion channels impair cell function, leading to periodic paralysis, cardiac arrhythmia, renal failure, epilepsy, migraine and ataxia1. Here we show that, in contrast with this well-established paradigm, three mutations in gating-charge-carrying arginine residues in an S4 segment that cause hypokalaemic periodic paralysis2 induce a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle NaV1.4 channel. This ‘gating pore current’ is active at the resting membrane potential and closed by depolarizations that activate the voltage sensor. It has similar permeability to Na+, K+ and Cs+, but the organic monovalent cations tetraethylammonium and N-methyl-d-glucamine are much less permeant. The inorganic divalent cations Ba2+, Ca2+ and Zn2+ are not detectably permeant and block the gating pore at millimolar concentrations. Our results reveal gating pore current in naturally occurring disease mutations of an ion channel and show a clear correlation between mutations that cause gating pore current and hypokalaemic periodic paralysis. This gain-of-function gating pore current would contribute in an important way to the dominantly inherited membrane depolarization, action potential failure, flaccid paralysis and cytopathology that are characteristic of hypokalaemic periodic paralysis. A survey of other ion channelopathies reveals numerous examples of mutations that would be expected to cause gating pore current, raising the possibility of a broader impact of gating pore current in ion channelopathies.

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Figure 1: Central pore Na + currents for wild-type Na v 1.4 and HypoPP mutant R666G channels.
Figure 2: Gating pore Na + currents for HypoPP mutant R666G channels.
Figure 3: Ion selectivity of R666G gating pore currents.
Figure 4: Gating pore Na + current in R663H and R666H HypoPP mutants.

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Acknowledgements

We thank E. M. Sharp for technical assistance in molecular biology. This work was funded by research grants from the National Institutes of Health and the Muscular Dystrophy Association to W.A.C.

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Correspondence to William A. Catterall.

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Sokolov, S., Scheuer, T. & Catterall, W. Gating pore current in an inherited ion channelopathy. Nature 446, 76–78 (2007). https://doi.org/10.1038/nature05598

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