General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA A receptor β3 subunit

Jurd, Rachel; Arrasa, Margarete; Lambert, Sachar; Drexler, Berthold; Siegwart, Roberta; Crestani, Florence; Zaugg, Michael; Vogt, Kaspar E.; Ledermann, Birgit; Antkowiak, Bernd; Rudolph, Uwe

doi:10.1096/fj.02-0611fje

Cited by 558Anesthesia and Sedative AgentsNeuroscience and Neuropharmacology ResearchAnesthesia and Neurotoxicity Research

General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA A receptor β3 subunit

Jurd, Rachel, Arrasa, Margarete, Lambert, Sachar, Drexler, Berthold, Siegwart, Roberta, Crestani, Florence, Zaugg, Michael, Vogt, Kaspar E. +3 more·2003·The FASEB Journal

DOI 10.1096/fj.02-0611fje

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Abstract

General anesthetics are widely used in clinical practice. On the molecular level, these compounds have been shown to modulate the activity of various neuronal ion channels. However, the functional relevance of identified sites in mediating essential components of the general anesthetic state, such as immobility and hypnosis, is still unknown. Using gene‐targeting technology, we generated mice harboring a subtle point mutation (N265M) in the second transmembrane region of the β3 subunit of the GABA A receptor. In these mice, the suppression of noxious‐evoked movements in response to the intravenous anesthetics etomidate and propofol is completely abolished, while only slightly decreased with the volatile anesthetics enflurane and halothane. β3(N265M) mice also display a profound reduction in the loss of righting reflex duration in response to intravenous but not volatile anesthetics. In addition, electrophysiological recordings revealed that anesthetic agents were significantly less effective in enhancing GABA A receptor‐mediated currents, and in decreasing spontaneous action potential firing in cortical brain slices derived from mutant mice. Taken together, our results demonstrate that a single molecular target, and indeed a specific residue (N265) located within the GABA A receptor β3 subunit, is a major determinant of behavioral responses evoked by the intravenous anesthetics etomidate and propofol, whereas volatile anesthetics appear to act via a broader spectrum of molecular targets.

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Anesthetic drugs bind directly to GABAA receptors, as shown by X-ray crystallography and high-resolution mass spectrometry.
“direct evidence of anesthetic drugs binding to GABAA receptors has been demonstrated both with X-ray crystallographic and high resolution mass spectrometry studies [35–37].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [37]

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PLASMA GLUTATHIONE S-TRANSFERASE CONCENTRATION AS A MEASURE OF HEPATOCELLULAR INTEGRITY FOLLOWING A SINGLE GENERAL ANAESTHETIC WITH HALOTHANE, ENFLURANE OR ISOFLURANE
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Authors: Jurd, R., Arrasa, M., Lambert, S., Drexler, B., Siegwart, R., Crestani, F., Zaugg, M., Vogt, K. E., Ledermann, B., Antkowiak, B., & Rudolph, U.
Affiliations: Institute of Pharmacology and Toxicology
University of Zurich (CH)
University of Tübingen (DE)
ORCID: Drexler, Berthold
Zaugg, Michael
Vogt, Kaspar E.
Rudolph, Uwe
Venue: The FASEB Journal
Publisher: Wiley
Published: 2002-12-03
Volume: 17
Issue: 2
Pages: 250-252
ISSN: 0892-6638 (ISSN-L)
1530-6860
DOI: 10.1096/fj.02-0611fje
OpenAlex: W2100231995
Cited by: 558
References: 57
Citations by year: 2026: 5 · 2025: 6 · 2024: 14 · 2023: 9 · 2022: 11 · 2021: 23 · 2020: 14 · 2019: 19 · 2018: 31 · 2017: 20 · 2016: 24 · 2015: 24 · 2014: 29 · 2013: 24 · 2012: 25
FWCI: 30.15
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: The FASEB Journal (publishedVersion)
PubMed (publishedVersion)
Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
Funders: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
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: general anesthetics, GABAA receptor, beta3 subunit, point mutations, etomidate, propofol, enflurane, halothane, intravenous anesthetics, volatile anesthetics, righting reflex
MeSH terms: Animals, Behavior, Animal, Brain, Dose-Response Relationship, Drug, Electrophysiology, Enflurane, Etomidate, Halothane, Mice, Inbred Strains, Receptors, GABA-A, Propofol, Point Mutation, Anesthetics, Inhalation, Anesthetics, Intravenous, Protein Subunits, Mice

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General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA A receptor β3 subunit

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