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A hERG Blocker Facilitates K+ Channel Current by Agonizing Pore Opening while Blocking.
Steffen S Docken1,2, Matthew J Marquis3, Khoa Ngo3
1Department of Mathematics, University of California, Davis, Davis, CA 95616, USA.
Biorxiv : the Preprint Server for Biology
|June 12, 2026
Summary
Many drugs blocking human Ether-à-go-go-Related Gene (hERG) channels can cause dangerous heart rhythms. This study reveals an "agonism-while-blocking" mechanism explains how some drugs, like nifekalant, increase hERG current, potentially improving safety.
Area of Science:
- Cardiovascular Pharmacology
- Molecular Cardiology
- Ion Channel Biophysics
Background:
- Drugs blocking human Ether-à-go-go-Related Gene (hERG) potassium channels can induce life-threatening cardiac arrhythmias.
- The molecular mechanisms underlying hERG channel block and associated risks are not fully understood.
- Facilitation, an increase in hERG current despite channel blockade, is observed with many hERG blockers and may counteract arrhythmogenic effects.
Purpose of the Study:
- To investigate the molecular mechanisms of hERG channel facilitation induced by blockers.
- To test the hypothesis that an 'agonism-while-blocking' mechanism underlies facilitation.
- To elucidate how nifekalant, a Class III antiarrhythmic drug, interacts with hERG channels.
Main Methods:
- Development of rate-theory kinetic models to simulate facilitation.
- Generation of atomistic models to predict drug-channel interactions.
- Performance of voltage-clamp electrophysiology experiments to measure hERG currents.
Main Results:
- The 'agonism-while-blocking' mechanism was identified as the basis for nifekalant-induced facilitation.
- Atomistic models predicted nifekalant modulates the intracellular gate while blocking the conduction path.
- Voltage-clamp data confirmed that agonism-while-blocking underlies both nifekalant block and facilitation.
Conclusions:
- The 'agonism-while-blocking' mechanism explains hERG channel facilitation by certain drugs.
- This mechanism may contribute to the improved safety profile of hERG blockers that exhibit facilitation.
- Understanding this mechanism could guide the development of safer cardiac drugs.
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