ArticleMolecular pharmacology2008
Tryptophan mutations at azi-etomidate photo-incorporation sites on alpha1 or beta2 subunits enhance GABAA receptor gating and reduce etomidate modulation.
Article in Molecular pharmacology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers.
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Who cites it
61 citing papers in PubMed, 81 citations in OpenAlex.
- Longrange PCR-based next-generation sequencing in pharmacokinetics and pharmacodynamics study of propofol among patients under general anaesthesia.Scientific reports · 2017Trial
- Φ value analysis underscores strong functional and structural compactness of the GABAProceedings of the National Academy of Sciences of the United States of America · 2025Article
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- Structural insights into GABANature communications · 2024Article
- Substituted Cysteine Modification and Protection with n-Alkyl-MTS Reagents Quantifies Steric Changes Induced by a Mutation in Anesthetic Binding Sites on GABA Type A Receptors.Molecular pharmacology · 2023Article
- Modulation of the mammalian GABABritish journal of pharmacology · 2022Article
- (+)-Catharanthine potentiates the GABABiochemical pharmacology · 2022Article
- Substituted Cysteine Modification and Protection withMolecular pharmacology · 2021Article
- Site-specific effects of neurosteroids on GABAeLife · 2020Article
- Monod-Wyman-Changeux Allosteric Shift Analysis in MutantMolecular pharmacology · 2019Article
- Application of the Co-Agonist Concerted Transition Model to Analysis of GABAA Receptor Properties.Current neuropharmacology · 2019Review
- Etomidate and Etomidate Analog Binding and Positive Modulation of γ-Aminobutyric Acid Type A Receptors: Evidence for a State-dependent Cutoff Effect.Anesthesiology · 2018Article
- Structural basis of neurosteroid anesthetic action on GABANature communications · 2018Article
- Article
- Comparison of αβδ and αβγ GABAPharmacological research · 2018Review
- High Constitutive Activity Accounts for the Combination of Enhanced Direct Activation and Reduced Potentiation in Mutated GABAMolecular pharmacology · 2018Article
- Propofol Is an Allosteric Agonist with Multiple Binding Sites on Concatemeric Ternary GABAMolecular pharmacology · 2018Article
- 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
- Synthesis and pharmacological evaluation of neurosteroid photoaffinity ligands.European journal of medicinal chemistry · 2017Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The potent general anesthetic etomidate produces its effects by enhancing GABA(A) receptor activation. Its photolabel analog [(3)H]azi-etomidate labels residues within transmembrane domains on alpha and beta subunits: alphaMet236 and betaMet286. We hypothesized that these methionines contribute to etomidate sites formed at alpha-beta subunit interfaces and that increasing side-chain bulk and hydrophobicity at either locus would mimic etomidate binding and block etomidate effects. Channel activity was electrophysiologically quantified in alpha(1)beta(2)gamma(2L) receptors with alpha(1)M236W or beta(2)M286W mutations, in both the absence and the presence of etomidate. Measurements included spontaneous activation, GABA EC(50), etomidate agonist potentiation, etomidate direct activation, and rapid macrocurrent kinetics. Both alpha(1)M236W and beta(2)M286W mutations induced spontaneous channel opening, lowered GABA EC(50), increased maximal GABA efficacy, and slowed current deactivation, mimicking effects of etomidate on alpha(1)beta(2)gamma(2L) channels. These changes were larger with alpha(1)M236W than with beta(2)M286W. Etomidate (3.2 muM) reduced GABA EC(50) much less in alpha(1)M236Wbeta(2)gamma(2L) receptors (2-fold) than in wild type (23-fold). However, etomidate was more potent and efficacious in directly activating alpha(1)M236Wbeta(2)gamma(2L) compared with wild type. In alpha(1)beta(2)M286Wgamma(2L) receptors, etomidate induced neither agonist-potentiation nor direct channel activation. These results support the hypothesis that alpha(1)Met236 and beta(2)Met286 are within etomidate sites that allosterically link to channel gating. Although alpha(1)M236W produced the larger impact on channel gating, beta(2)M286W produced more profound changes in etomidate sensitivity, suggesting a dominant role in drug binding. Furthermore, quantitative mechanistic analysis demonstrated that wild-type and mutant results are consistent with the presence of only one class of etomidate sites mediating both agonist potentiation and direct activation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.