Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity
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Significance: Molecular mechanisms of general anesthetic modulation in pentameric ligand-gated ion channels remain controversial. Here we present molecular simulations and functional data that reveal correlations between dynamic differences in a membrane-accessible cavity and dramatic anesthetic effects, separate inhibitory and potentiating effects within the same electrophysiology recordings, and support a model for communication between the lipid bilayer and ion channel pore. In particular, enhanced electrostatic interactions in the membrane-accessible site were associated with a unique mode of anesthetic potentiation, persisting tens of minutes after washout. These results offer a bridge between lipid- and receptor-based theories of anesthesia, with the potential to inform both mechanistic understanding and drug development.
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Anesthetic actions on pLGICs are not limited to GABAA receptors and are not unique to mammals.
“Anesthetic actions on pLGICs are not limited solely to GABAA receptors [41–44] and the modulatory actions of anesthetics on pLGIC family members are not unique to mammalian systems [45, 46].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [46]
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References 55 · Cited by 23
- Authors
- Heusser, S. A., Lycksell, M., Wang, X., McComas, S. E., Howard, R. J., & Lindahl, E.
- Affiliations
- Stockholm University (SE)
- Corresponding author
- Lindahl, Erik
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-10
- Volume
- 115
- Issue
- 42
- Pages
- 10672-10677
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6196478
- OpenAlex
- W2894186226
- Cited by
- 23
- References
- 55
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 6 · 2020: 5 · 2019: 5
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Knut och Alice Wallenbergs Stiftelse (n/a)
- Swedish eScience Research Centre (n/a)
- Swedish Foundation for Strategic Research (Swedish National Graduate School for Neutron Scattering)
- Swedish Research Council (2017-04641)
- Swedish National Infrastructure for Computing (2017-12/54)
- BioExcel H2020 Center-of-Excellence for Computational Biomolecular Research (675728)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- general anesthesia, ligand-gated ion channels, GLIC, propofol, pentameric ligand-gated ion channels, anesthetic binding sites, allosteric modulation
- MeSH terms
- Cyanobacteria, Allosteric Regulation, Binding Sites, Cell Membrane, Ligands, Membrane Potentials, Models, Molecular, Protein Binding, Ion Channel Gating, Propofol, Anesthetics, Intravenous, Molecular Dynamics Simulation, Ligand-Gated Ion Channels
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