A conserved conformation-dependent mechanism for the TREK two-pore domain potassium channel inhibitors carvedilol and fluphenazine
6 affiliations
- 1Center for Advanced Biotechnology and Medicine, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, Piscataway, New Jersey
- 2Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, Piscataway, New Jersey
- 3Department of Medicine, Robert Wood Johnson Medical School, Rutgers, the State University of New Jersey, Piscataway, New Jersey
- 4Department of Anesthesiology, Weill Cornell Medical College, New York, New York
- 5Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, United Kingdom
- 6Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, United Kingdom
Abstract
The TREK subfamily of 2-pore domain potassium channels act as polymodal sensors of multiple physical and chemical stimuli, coupling electrical excitability to the cellular environment. A nuanced understanding of TREK channel pharmacology is necessary for the development of novel experimental tools, for potential pharmacotherapies, and for understanding potential beneficial or adverse effects of clinically used drugs. Here, we sought to determine the mechanism of action of 2 TREK channel inhibitors: the β-blocker carvedilol and the antipsychotic fluphenazine. Using patch and 2-electrode voltage-clamp electrophysiology, we show that both carvedilol and fluphenazine exhibit an activation-mode dependence, with mechanical- and temperature-activation of TREK channels reducing drug sensitivity approximately 10-fold. Mutagenesis at a key intramembrane fenestration site leucine, modulator competition experiments, and in silico docking studies are all consistent with carvedilol and fluphenazine binding at a shared, overlapping binding site. These findings establish a conserved conformation-dependent mechanism of action for structurally diverse TREK inhibitors and identify the fenestration as a promiscuous binding site for a range of clinically used drugs.
Significance Statement: TREK potassium channels play key roles in regulating membrane excitability in a wide range of cells. Modulation of these channels has been proposed for potential antiarrhythmic and antidepressant effects. This study defined the off-target molecular mechanism of action of the clinically used drugs carvedilol and fluphenazine on TREK channels and identify the TREK channel fenestration as a promiscuous binding site for inhibitory drugs.
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BibTeX
@article{reich2026conserved,
title = {{A conserved conformation-dependent mechanism for the TREK two-pore domain potassium channel inhibitors carvedilol and fluphenazine}},
author = {Joelle Reich and Paul M. Riegelhaupt and Stephen J. Tucker and Conor McClenaghan},
journal = {Molecular Pharmacology},
year = {2026},
month = sep,
doi = {10.1016/j.molpha.2026.100155},
url = {https://doi.org/10.1016/j.molpha.2026.100155},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A conserved conformation-dependent mechanism for the TREK two-pore domain potassium channel inhibitors carvedilol and fluphenazine
AU - Joelle Reich
AU - Paul M. Riegelhaupt
AU - Stephen J. Tucker
AU - Conor McClenaghan
PY - 2026
DA - 2026/09/12
JO - Molecular Pharmacology
DO - 10.1016/j.molpha.2026.100155
UR - https://doi.org/10.1016/j.molpha.2026.100155
AB - The TREK subfamily of 2-pore domain potassium channels act as polymodal sensors of multiple physical and chemical stimuli, coupling electrical excitability to the cellular environment. A nuanced understanding of TREK channel pharmacology is necessary for the development of novel experimental tools, for potential pharmacotherapies, and for understanding potential beneficial or adverse effects of clinically used drugs. Here, we sought to determine the mechanism of action of 2 TREK channel inhibitors: the β-blocker carvedilol and the antipsychotic fluphenazine. Using patch and 2-electrode voltage-clamp electrophysiology, we show that both carvedilol and fluphenazine exhibit an activation-mode dependence, with mechanical- and temperature-activation of TREK channels reducing drug sensitivity approximately 10-fold. Mutagenesis at a key intramembrane fenestration site leucine, modulator competition experiments, and in silico docking studies are all consistent with carvedilol and fluphenazine binding at a shared, overlapping binding site. These findings establish a conserved conformation-dependent mechanism of action for structurally diverse TREK inhibitors and identify the fenestration as a promiscuous binding site for a range of clinically used drugs. Significance Statement: TREK potassium channels play key roles in regulating membrane excitability in a wide range of cells. Modulation of these channels has been proposed for potential antiarrhythmic and antidepressant effects. This study defined the off-target molecular mechanism of action of the clinically used drugs carvedilol and fluphenazine on TREK channels and identify the TREK channel fenestration as a promiscuous binding site for inhibitory drugs.
SN - 0026-895X
SN - 1521-0111
ER -