{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T02:13:57Z","timestamp":1789352037493,"version":"build-2803163510"},"reference-count":45,"publisher":"Rockefeller University Press","issue":"2","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2010,8,1]]},"abstract":"<jats:p>Hypokalemic periodic paralysis and normokalemic periodic paralysis are caused by mutations of the gating charge\u2013carrying arginine residues in skeletal muscle NaV1.4 channels, which induce gating pore current through the mutant voltage sensor domains. Inward sodium currents through the gating pore of mutant R666G are only \u223c1% of central pore current, but substitution of guanidine for sodium in the extracellular solution increases their size by 13- \u00b1 2-fold. Ethylguanidine is permeant through the R666G gating pore at physiological membrane potentials but blocks the gating pore at hyperpolarized potentials. Guanidine is also highly permeant through the proton-selective gating pore formed by the mutant R666H. Gating pore current conducted by the R666G mutant is blocked by divalent cations such as Ba2+ and Zn2+ in a voltage-dependent manner. The affinity for voltage-dependent block of gating pore current by Ba2+ and Zn2+ is increased at more negative holding potentials. The apparent dissociation constant (Kd) values for Zn2+ block for test pulses to \u2212160 mV are 650 \u00b1 150 \u00b5M, 360 \u00b1 70 \u00b5M, and 95.6 \u00b1 11 \u00b5M at holding potentials of 0 mV, \u221280 mV, and \u2212120 mV, respectively. Gating pore current is blocked by trivalent cations, but in a nearly voltage-independent manner, with an apparent Kd for Gd3+ of 238 \u00b1 14 \u00b5M at \u221280 mV. To test whether these periodic paralyses might be treated by blocking gating pore current, we screened several aromatic and aliphatic guanidine derivatives and found that 1-(2,4-xylyl)guanidinium can block gating pore current in the millimolar concentration range without affecting normal NaV1.4 channel function. Together, our results demonstrate unique permeability of guanidine through NaV1.4 gating pores, define voltage-dependent and voltage-independent block by divalent and trivalent cations, respectively, and provide initial support for the concept that guanidine-based gating pore blockers could be therapeutically useful.<\/jats:p>","DOI":"10.1085\/jgp.201010414","type":"journal-article","created":{"date-parts":[[2010,7,26]],"date-time":"2010-07-26T19:07:41Z","timestamp":1280171261000},"page":"225-236","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":65,"title":["Ion permeation and block of the gating pore in the voltage sensor of NaV1.4 channels with hypokalemic periodic paralysis mutations"],"prefix":"10.1085","volume":"136","author":[{"given":"Stanislav","family":"Sokolov","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Scheuer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Catterall","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2010,7,26]]},"reference":[{"key":"2023072622082215800_bib1","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1152\/physrev.1981.61.3.644","article-title":"Sodium channels and gating currents","volume":"61","author":"Armstrong","year":"1981","journal-title":"Physiol. 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