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Sedation and Anesthesia Mediated by Distinct GABA A Receptor Isoforms
Open accessAbstract
The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABA A receptors, with selectivity for β2 and β3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive β2 subunit (β2 N265S) to determine the role of β2 and β3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through β3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the β2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABA A receptor subtypes.
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“Convincing evidence for a contribution of GABAA receptors to important anesthetic actions such as sedation, hypnosis, hypothermia, and immobility have come from experiments on knock-in mice, in which point mutations that abolish anesthetic binding sites also curtail the behavioral effects of several anesthetics [38, 39].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [38]
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Metadata
- Authors
- Reynolds, D. S., Rosahl, T. W., Cirone, J., O'Meara, G. F., Haythornthwaite, A., Newman, R. J., Myers, J., Sur, C., Howell, O., Rutter, A. R., Atack, J., Macaulay, A. J., Hadingham, K. L., Hutson, P. H., Belelli, D., Lambert, J. J., Dawson, G. R., McKernan, R., Whiting, P. J., & Wafford, K. A.
- Affiliations
- University of Dundee (GB)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2003-09-17
- Volume
- 23
- Issue
- 24
- Pages
- 8608-8617
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6740367
- OpenAlex
- W2140230931
- Cited by
- 318
- References
- 35
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 9 · 2020: 11 · 2019: 9 · 2018: 12 · 2017: 7 · 2016: 14 · 2015: 8 · 2014: 10 · 2013: 8 · 2012: 6
- FWCI
- 32.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- PubMed
- Funders
- Directorate for Biological Sciences
- Medical Research Council
- Topics
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Keywords
- GABAA receptor, etomidate, general anesthesia, sedation, beta2 subunit, beta3 subunit, loss of consciousness, burst suppression, anesthesia recovery
- MeSH terms
- Anesthetics, Animals, Anticonvulsants, Behavior, Animal, Binding, Competitive, Cell Separation, Consciousness, Dose-Response Relationship, Drug, Electroencephalography, Etomidate, Hypnotics and Sedatives, Male, Mice, Mutant Strains, Motor Activity, Purkinje Cells, Receptors, GABA-A, Triazoles, Gene Targeting, Patch-Clamp Techniques, Bridged Bicyclo Compounds, Heterocyclic, Protein Isoforms, Recovery of Function, Mice, In Vitro Techniques
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