Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics
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Alcohols and other anesthetic agents dramatically alter neurologic function in a wide range of organisms, yet their molecular sites of action remain poorly characterized. Pentameric ligand-gated ion channels, long implicated in important direct effects of alcohol and anesthetic binding, have recently been illuminated in renewed detail thanks to the determination of atomic-resolution structures of several family members from lower organisms. These structures provide valuable models for understanding and developing anesthetic agents and for allosteric modulation in general. This review surveys progress in this field from function to structure and back again, outlining early evidence for relevant modulation of pentameric ligand-gated ion channels and the development of early structural models for ion channel function and modulation. We highlight insights and challenges provided by recent crystal structures and resulting simulations, as well as opportunities for translation of these newly detailed models back to behavior and therapy.
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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 [43]
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Self-citationThe TM2 6′ Position of GABAA Receptors Mediates Alcohol Inhibition
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Towards a comprehensive understanding of anesthetic mechanisms of action: a decade of discovery
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Self-citation
- Authors
- Howard, R. J., Trudell, J. R., & Harris, R. A.
- Affiliations
- Skidmore College (US)
- Venue
- Pharmacological Reviews
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 66
- Issue
- 2
- Pages
- 396-412
- ISSN
- 0031-6997 (ISSN-L)
- PMC
- PMC3973611
- OpenAlex
- W2124771139
- Cited by
- 56
- References
- 185
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 2 · 2022: 4 · 2020: 4 · 2019: 4 · 2018: 7 · 2017: 12 · 2016: 9 · 2015: 5 · 2014: 6
- FWCI
- 1.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Pharmacological Reviews (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Creative Matter (Skidmore College) (submittedVersion)
- Funders
- Skidmore College
- National Institutes of Health (5r01aa006399-36, AA06399)
- National Institute on Alcohol Abuse and Alcoholism (R01-AA006399, R01-AA06399, R01AA013378, R01AA020980)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- pentameric ligand-gated ion channels, general anesthetics, alcohol, allosteric modulation, ion channel structure, crystal structure, anesthetic binding, ion channel function
- MeSH terms
- Alcohols, Animals, Behavior, Animal, Binding Sites, Humans, Ligands, Protein Binding, Protein Conformation, Drug Design, Crystallography, X-Ray, Anesthetics, General, Alcohol-Related Disorders, Molecular Dynamics Simulation, Ligand-Gated Ion Channels
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