Disrupted coupling of gating charge displacement to Na+ current activation for DIIS4 mutations in hypokalemic periodic paralysis.

Abstract

Missense mutations at arginine residues in the S4 voltage-sensor domains of NaV1.4 are an established cause of hypokalemic periodic paralysis, an inherited disorder of skeletal muscle involving recurrent episodes of weakness in conjunction with low serum K(+). Expression studies in oocytes have revealed anomalous, hyperpolarization-activated gating pore currents in mutant channels. This aberrant gating pore conductance creates a small inward current at the resting potential that is thought to contribute to susceptibility to depolarization in low K(+) during attacks of weakness. A critical component of this hypothesis is the magnitude of the gating pore conductance relative to other conductances that are active at the resting potential in mammalian muscle: large enough to favor episodes of paradoxical depolarization in low K(+), yet not so large as to permanently depolarize the fiber. To improve the estimate of the specific conductance for the gating pore in affected muscle, we sequentially measured Na(+) current through the channel pore, gating pore current, and gating charge displacement in oocytes expressing R669H, R672G, or wild-type NaV1.4 channels. The relative conductance of the gating pore to that of the pore domain pathway for Na(+) was 0.03%, which implies a specific conductance in muscle from heterozygous patients of ∼ 10 µS/cm(2) or 1% of the total resting conductance. Unexpectedly, our data also revealed a substantial decoupling between gating charge displacement and peak Na(+) current for both R669H and R672G mutant channels. This decoupling predicts a reduced Na(+) current density in affected muscle, consistent with the observations that the maximal dV/dt and peak amplitude of the action potential are reduced in fibers from patients with R672G and in a knock-in mouse model of R669H. The defective coupling between gating charge displacement and channel activation identifies a previously unappreciated mechanism that contributes to the reduced excitability of affected fibers seen with these mutations and possibly with other R/X mutations of S4 of NaV, CaV, and KV channels associated with human disease.

• Authors: Wentao Mi, Volodymyr Rybalchenko, Stephen C Cannon
• Journal: The Journal of general physiology (J Gen Physiol) Vol. 144 Issue 2 Pg. 137-45 (Aug 2014) ISSN: 1540-7748 [Electronic] United States
• PMID: 25024265 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Mi et al.

Chemical References

• NAV1.4 Voltage-Gated Sodium Channel
• SCN4A protein, human
• Sodium Channels

Topics

• Action Potentials
• Animals
• Gene Knock-In Techniques
• Humans
• Hypokalemic Periodic Paralysis (genetics, metabolism, physiopathology)
• Ion Channel Gating (genetics)
• Mice
• Mutation (genetics)
• NAV1.4 Voltage-Gated Sodium Channel (metabolism)
• Oocytes (metabolism)
• Patch-Clamp Techniques
• Sodium Channels (genetics, metabolism)
• Xenopus laevis