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

Many drugs that block voltage-gated K+ channels encoded by the human Ether-a-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.