Interplay between VSD, pore and membrane lipids in electromechanical coupling in HCN channels
- KTH Royal Institute of Technology, Sweden
- Washington University in St. Louis, United States
Abstract
Hyperpolarized-activated and Cyclic Nucleotide-gated (HCN) channels are the only members of the voltage-gated ion channel superfamily in mammals that open upon hyperpolarization, conferring them pacemaker properties that are instrumental for rhythmic firing of cardiac and neuronal cells. Activation of their voltage-sensor domains (VSD) upon hyperpolarization occurs through a downward movement of the S4 helix bearing the gating charges, which triggers a break in the alpha-helical hydrogen bonding pattern at the level of a conserved Serine residue. Previous structural and molecular simulation studies had however failed to capture pore opening that should be triggered by VSD activation, presumably because of a low VSD/pore electromechanical coupling efficiency and the limited timescales accessible to such techniques. Here, we have used advanced modeling strategies, including enhanced sampling molecular dynamics simulations exploiting comparisons between non-domain swapped voltage-gated ion channel structures trapped in closed and open states to trigger pore gating and characterize electromechanical coupling in HCN1. We propose that the coupling mechanism involves the reorganization of the interfaces between the VSD helices, in particular S4, and the pore-forming helices S5 and S6, subtly shifting the balance between hydrophobic and hydrophilic interactions in a 'domino effect' during activation and gating in this region. Remarkably, our simulations reveal state-dependent occupancy of lipid molecules at this emergent coupling interface, suggesting a key role of lipids in hyperpolarization-dependent gating. Our model provides a rationale for previous observations and a possible mechanism for regulation of HCN channels by the lipidic components of the membrane.
Data availability
The files containing the raw data for the modeling/computational part of the study can be found at the following link: https://zenodo.org/record/7920679#.ZFyJW-zRY-SThe scripts used to analyze the MD simulations can be found at https://github.com/elbahnsi/ELIFE-Interplay-between-VSD-pore-and-membrane-lipids-in-electromechanical-coupling-in-HCN-channelsAll data generated or analyzed during the experimental part of the study are included in the manuscript.
Article and author information
Author details
Funding
Science for Life Laboratory
- Lucie Delemotte
Gustafsson foundation
- Lucie Delemotte
Vetenskapsrådet (2018-04905)
- Lucie Delemotte
Vetenskapsrådet (2019-02433)
- Lucie Delemotte
Vetenskapsrådet (2022-04305)
- Lucie Delemotte
National Institute of Neurological Disorders and Stroke (1R35NS116850)
- Baron Chanda
Austrian Science Foundation (J4652)
- Verena Burtscher
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Elbahnsi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Interplay between VSD, pore and membrane lipids in electromechanical coupling in HCN channels
eLife 12:e80303.
https://doi.org/10.7554/eLife.80303
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