Anesthetics target interfacial transmembrane sites in nicotinic acetylcholine receptors

Forman, Stuart A.; Chiara, David C.; Miller, Keith W.

doi:10.1016/j.neuropharm.2014.10.002

Cited by 42Nicotinic Acetylcholine Receptors StudyNeuroscience and Neuropharmacology ResearchAnesthesia and Sedative Agents

Anesthetics target interfacial transmembrane sites in nicotinic acetylcholine receptors

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Forman, Stuart A., Chiara, David C., Miller, Keith W.·2015·Neuropharmacology

DOI 10.1016/j.neuropharm.2014.10.002PMC PMC4394016

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Abstract

General anesthetics are a heterogeneous group of small amphiphilic ligands that interact weakly at multiple allosteric sites on many pentameric ligand gated ion channels (pLGICs), resulting in either inhibition, potentiation of channel activity, or both. Allosteric principles imply that modulator sites must change configuration and ligand affinity during receptor state transitions. Thus, general anesthetics and related compounds are useful both as state-dependent probes of receptor structure and as potentially selective modulators of pLGIC functions. This review focuses on general anesthetic sites in nicotinic acetylcholine receptors, which were among the first anesthetic-sensitive pLGIC experimental models studied, with particular focus on sites formed by transmembrane domain elements. Structural models place many of these sites at interfaces between two or more pLGIC transmembrane helices both within subunits and between adjacent subunits, and between transmembrane helices and either lipids (the lipid-protein interface) or water (i.e. the ion channel). A single general anesthetic may bind at multiple allosteric sites in pLGICs, producing a net effect of either inhibition (e.g. blocking the ion channel) or enhanced channel gating (e.g. inter-subunit sites). Other general anesthetic sites identified by photolabeling or crystallography are tentatively linked to functional effects, including intra-subunit helix bundle sites and the lipid-protein interface. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.

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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 [41]

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Authors: Forman, S. A., Chiara, D. C., & Miller, K. W.
Affiliations: Harvard University (US)
Corresponding author: Forman, Stuart A.
ORCID: Forman, Stuart A.
Miller, Keith W.
Venue: Neuropharmacology
Publisher: Elsevier BV
Published: 2015-09
Volume: 96
Issue: Pt B
Pages: 169-177
ISSN: 0028-3908 (ISSN-L)
DOI: 10.1016/j.neuropharm.2014.10.002
PMC: PMC4394016
OpenAlex: W2056319725
Cited by: 42
References: 101
Citations by year: 2025: 2 · 2024: 2 · 2023: 4 · 2022: 1 · 2021: 1 · 2020: 3 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 8 · 2015: 2 · 2014: 1
FWCI: 0.53
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuropharmacology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (P01GM58448, R01GM89745)
NIGMS (P41-GM103311)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
Keywords: general anesthetics, nicotinic acetylcholine receptors, pentameric ligand-gated ion channels, allosteric site, protein-lipid interface, channel gating, anesthetic binding sites
MeSH terms: Allosteric Regulation, Allosteric Site, Animals, Brain, Humans, Neurons, Receptors, Nicotinic, Protein Structure, Secondary, Muscle, Skeletal, Anesthetics, General, Nicotinic Agonists

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Anesthetics target interfacial transmembrane sites in nicotinic acetylcholine receptors

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