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A process that may counteract arrhythmogenic hERG block, termed facilitation, is common to many clinically approved hERG blockers, including nifekalant, amiodarone, promethazine, imipramine, nortriptyline, haloperidol, verapamil, carvedilol, metoprolol, propranolol, quinidine, fluoxetine, and chlorpheniramine. Facilitation is an increase in hERG current, under certain conditions, due to these blockers. Here, we propose that an agonism-while-blocking mechanism underpins facilitation. We focus on nifekalant, a class III antiarrhythmic drug and exemplar hERG blocker that induces facilitation. We tested the hypothesis that nifekalant opens hERG channel gates while blocking, and that unblocking of these open-yet-blocked channels results in supranormal hERG current. We developed rate-theory kinetic models to identify features of agonism-while-blocking that produce facilitation. We generated atomistic models that predict that nifekalant blocks the hERG conduction path while modulating the intracellular conduction gate. Voltage-clamp measurements revealed that agonism-while-blocking can result in nifekalant block and facilitation. We speculate that this agonism-while-blocking mechanism contributes to the relative safety of hERG blockers that induce facilitation.<\/jats:p>","DOI":"10.1085\/jgp.202614015","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:20:31Z","timestamp":1786515631000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["A hERG blocker facilitates K+ channel current by promoting pore opening while blocking"],"prefix":"10.1085","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3771-5504","authenticated-orcid":true,"given":"Steffen S.","family":"Docken","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05rrcem69","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Davis 1 Department of Mathematics, , Davis, CA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/03r8z3t63","id-type":"ROR","asserted-by":"publisher"}],"name":"Kirby 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