{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T02:13:58Z","timestamp":1789352038980,"version":"build-2803163510"},"reference-count":25,"publisher":"Rockefeller University Press","issue":"2","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,8,1]]},"abstract":"<jats:p>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 \u223c10 \u00b5S\/cm2 or 1% of the total resting conductance.<\/jats:p>\n               <jats:p>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.<\/jats:p>","DOI":"10.1085\/jgp.201411199","type":"journal-article","created":{"date-parts":[[2014,7,15]],"date-time":"2014-07-15T01:38:39Z","timestamp":1405388319000},"page":"137-145","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Disrupted coupling of gating charge displacement to Na+ current activation for DIIS4 mutations in hypokalemic periodic paralysis"],"prefix":"10.1085","volume":"144","author":[{"given":"Wentao","family":"Mi","sequence":"first","affiliation":[{"name":"Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volodymyr","family":"Rybalchenko","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen C.","family":"Cannon","sequence":"additional","affiliation":[{"name":"Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2014,7,14]]},"reference":[{"key":"2023072623191863900_bib1","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1085\/jgp.63.5.533","article-title":"Charge movement associated with the opening and closing of the activation gates of the Na channels","volume":"63","author":"Armstrong","year":"1974","journal-title":"J. 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