ArticleAnesthesiology2009
Gamma-amino butyric acid type A receptor mutations at beta2N265 alter etomidate efficacy while preserving basal and agonist-dependent activity.
Article in Anesthesiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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40 citing papers in PubMed, 61 citations in OpenAlex.
- Behavioral studies of the abuse potential and anesthetic and sedative effects of etomidate in male rodents.Psychopharmacology · 2025Article
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- Bilirubin potentiates etomidate-induced sedation by enhancing GABA-induced currents after bile duct ligation.BMC pharmacology & toxicology · 2023Article
- Changes in Memory, Sedation, and Receptor Kinetics Imparted by the β2-N265M and β3-N265M GABAInternational journal of molecular sciences · 2023Article
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- A potent photoreactive general anesthetic with novel binding site selectivity for GABAEuropean journal of medicinal chemistry · 2020Article
- GABAInternational journal of molecular sciences · 2020Article
- Personalized pediatric anesthesia and pain management: problem-based review.Pharmacogenomics · 2020Review
- Drug-selective Anesthetic Insensitivity of Zebrafish Lacking γ-Aminobutyric Acid Type A Receptor β3 Subunits.Anesthesiology · 2019Article
- Monod-Wyman-Changeux Allosteric Shift Analysis in MutantMolecular pharmacology · 2019Article
- Comparison of αβδ and αβγ GABAPharmacological research · 2018Review
- Alphaxalone Binds in Inner Transmembrane β+-α- Interfaces of α1β3γ2 γ-Aminobutyric Acid Type A Receptors.Anesthesiology · 2018Article
- Combining Mutations and Electrophysiology to Map Anesthetic Sites on Ligand-Gated Ion Channels.Methods in enzymology · 2018Review
- Orthosteric- versus allosteric-dependent activation of the GABAScientific reports · 2017Article
- Novel Molecule Exhibiting Selective Affinity for GABAScientific reports · 2017Article
- γ-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs.Anesthesiology · 2016Article
- A Cysteine Substitution Probes β3H267 Interactions with Propofol and Other Potent Anesthetics in α1β3γ2L γ-Aminobutyric Acid Type A Receptors.Anesthesiology · 2016Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
backgroundEtomidate acts at gamma-Aminobutyric acid type A (GABAA) receptors containing beta2 or beta3, but not beta1 subunits. Mutations at beta residue 265 (Ser in beta1; Asn in beta2 or beta3) profoundly affect etomidate sensitivity. Whether these mutations alter etomidate binding remains uncertain.
methodsHeterologously expressed alpha1beta2gamma2L GABAA receptors and receptors with beta2(N265S) or beta2(N265M) mutations were studied electrophysiologically in both Xenopus oocytes and HEK293 cells. Experiments quantified the impact of beta2N265 mutations or substituting beta1 for beta2 on basal channel activation, GABA EC50, maximal GABA efficacy, etomidate-induced leftward shift in GABA responses, etomidate direct activation, and rapid macrocurrent kinetics. Results were analyzed in the context of an established allosteric co-agonist mechanism.
resultsMutations produced only small changes in basal channel activity, GABA EC50, maximal GABA efficacy, and macrocurrent kinetics. Relative to wild-type, beta2(N265S) reduced etomidate enhancement of apparent GABA affinity six-fold, and it reduced etomidate direct activation efficacy 14-fold. beta2(N265M) totally eliminated both etomidate modulation of GABA responses and direct channel activation. Mechanism-based analysis showed that the function of both mutants remains consistent with the allosteric co-agonist model and that beta2(N265S) reduced etomidate allosteric efficacy five-fold, whereas etomidate-binding affinity dropped threefold. Experiments swapping beta2 subunits for beta1 indicated that etomidate efficacy is reduced 34-fold, whereas binding affinity drops less than two-fold.
conclusionsMutations at beta2N265 profoundly alter etomidate sensitivity with only small changes in basal and GABA-dependent channel activity. Mutations at the beta2N265 residue or replacement of beta2 with beta1 influence etomidate efficacy much more than binding to inactive receptors.
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