A hERG Blocker Facilitates K + Channel Current by Agonizing Pore Opening while Blocking

Year: 2026

Type: preprint

Abstract: channels encoded by the human Ether-à-go-go-Related Gene (hERG) can cause long QT syndrome and life-threatening cardiac arrhythmias, yet the molecular mechanisms that determine this risk remain unclear. 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 undergirds 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 unblock of these open-yet-blocked channels results in supranormal hERG current. We develop rate-theory kinetic models to identify features of agonism-while-blocking that produce facilitation. We generate atomistic models that predict that nifekalant blocks the hERG conduction path while modulating the intracellular conduction gate. Voltage-clamp measurements reveal that agonism-while-blocking undergirds nifekalant block and facilitation. We speculate that this agonism-while-blocking mechanism contributes to the relative safety of hERG blockers that induce facilitation.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.05.30.728541

Authors: Steffen S. Docken, Matthew J. Marquis, Khoa Ngo, Yuumu Wada, Satomi Kita, Vladimir Yarov-Yarovoy, Colleen E. Clancy, Igor Vorobyov, Timothy J. Lewis, Kazuharu Furutani, Jon T. Sack

Institutions: UNSW Sydney, Kirby Institute, University of California, Davis, Tokushima Bunri University

Language: English

Topic: Ion channel regulation and function

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Science Foundation, Ministry of Education, Culture, Sports, Science and Technology, National Institutes of Health, University of California, Davis, Japan Society for the Promotion of Science, Office of Advanced Cyberinfrastructure, Common Fund

OpenAlex ID: W7163344533