Cross-talk of filter gate and lower helices drives polymodal regulation and disease in TREK channels.
16 affiliations
- 1Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.
- 2Insitute of Chemistry, Technical University of Berlin, Berlin, Germany.
- 3School of Pharmaceutical Sciences, University of Geneva, Rue Michel Servet 1, Genève, Switzerland. [email protected].
- 4Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Genève, Switzerland. [email protected].
- 5Swiss Institute of Bioinformatics, University of Geneva, Genève, Switzerland. [email protected].
- 6Institute of Physiology, Kiel University, Kiel, Germany.
- 7School of Pharmaceutical Sciences, University of Geneva, Rue Michel Servet 1, Genève, Switzerland.
- 8Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Genève, Switzerland.
- 9Swiss Institute of Bioinformatics, University of Geneva, Genève, Switzerland.
- 10Institute of Physiology, Kiel University, Kiel, Germany. [email protected].
- 11School of Pharmaceutical Sciences, University of Geneva, Rue Michel Servet 1, Genève, Switzerland. [email protected].
- 12Institute of Pharmaceutical Sciences of Western Switzerland (ISPSO), University of Geneva, Genève, Switzerland. [email protected].
- 13Swiss Institute of Bioinformatics, University of Geneva, Genève, Switzerland. [email protected].
- 14Department of Chemistry, University College London, London, United Kingdom. [email protected].
- 15Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany. [email protected].
- 16Insitute of Chemistry, Technical University of Berlin, Berlin, Germany. [email protected].
Abstract
The TREK two-pore domain potassium channels regulate membrane excitability and respond to diverse physiological stimuli. Single-site mutations of TREK are associated with neurodevelopmental disorders and can cause pathological channel hyperactivation. Here, using the OneOPES enhanced-sampling molecular dynamics framework, we characterize the energetics of conformational transition along a predefined pathway connecting the up and down states of TREK-2, together with initial conformational rearrangements of the selectivity filter under physiological stimuli and disease-mimicking conditions. The simulations reveal a shared energetic axis coupling the lower helices, proximal C-terminus, and selectivity filter to govern channel gating. Predicted conformational effects of a disease-mimicking mutation were validated electrophysiologically using a conformation-sensitive TREK-2 inhibitor. Together with our previous unbiased MD simulations, these results establish an energetic framework for TREK-2 regulation and dysfunction, complementing prior structural and mechanistic studies while highlighting the potential and methodological challenges of advanced enhanced-sampling approaches for resolving complex conformational landscapes of ion channels.
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BibTeX
@article{turkaydin2026crosstalk,
title = {{Cross-talk of filter gate and lower helices drives polymodal regulation and disease in TREK channels.}},
author = {Berke Türkaydin and Valerio Rizzi and Chaimae Benkerdagh and Simon Ghysbrecht and Simone Aureli and Thomas Baukrowitz and Marcus Schewe and Francesco Luigi Gervasio and Han Sun},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77935-w},
url = {https://europepmc.org/article/MED/42907444},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cross-talk of filter gate and lower helices drives polymodal regulation and disease in TREK channels.
AU - Berke Türkaydin
AU - Valerio Rizzi
AU - Chaimae Benkerdagh
AU - Simon Ghysbrecht
AU - Simone Aureli
AU - Thomas Baukrowitz
AU - Marcus Schewe
AU - Francesco Luigi Gervasio
AU - Han Sun
PY - 2026
DA - 2026/09/22
JO - Nature communications
DO - 10.1038/s41467-026-77935-w
UR - https://europepmc.org/article/MED/42907444
AB - The TREK two-pore domain potassium channels regulate membrane excitability and respond to diverse physiological stimuli. Single-site mutations of TREK are associated with neurodevelopmental disorders and can cause pathological channel hyperactivation. Here, using the OneOPES enhanced-sampling molecular dynamics framework, we characterize the energetics of conformational transition along a predefined pathway connecting the up and down states of TREK-2, together with initial conformational rearrangements of the selectivity filter under physiological stimuli and disease-mimicking conditions. The simulations reveal a shared energetic axis coupling the lower helices, proximal C-terminus, and selectivity filter to govern channel gating. Predicted conformational effects of a disease-mimicking mutation were validated electrophysiologically using a conformation-sensitive TREK-2 inhibitor. Together with our previous unbiased MD simulations, these results establish an energetic framework for TREK-2 regulation and dysfunction, complementing prior structural and mechanistic studies while highlighting the potential and methodological challenges of advanced enhanced-sampling approaches for resolving complex conformational landscapes of ion channels.
SN - 2041-1723
ER -