ArticleThe Journal of biological chemistry2013
Specificity of intersubunit general anesthetic-binding sites in the transmembrane domain of the human α1β3γ2 γ-aminobutyric acid type A (GABAA) receptor.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers.
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Who cites it
85 citing papers in PubMed, 131 citations in OpenAlex.
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- Mutational Analysis of Anesthetic Binding Sites and Their Effects on GABABiomolecules · 2023Article
- Benzodiazepine-induced anterograde amnesia: detrimental side effect to novel study tool.Frontiers in pharmacology · 2023Review
- Modulation of the mammalian GABABritish journal of pharmacology · 2022Article
- Photomotor Responses in Zebrafish and Electrophysiology Reveal Varying Interactions of Anesthetics Targeting Distinct Sites on γ-Aminobutyric Acid Type A Receptors.Anesthesiology · 2022Article
- GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAPharmacology & therapeutics · 2022Review
- Pharmacological management of severe Cushing's syndrome: the role of etomidate.Therapeutic advances in endocrinology and metabolism · 2022Review
- Selective actions of benzodiazepines at the transmembrane anaesthetic binding sites of the GABABritish journal of pharmacology · 2021Article
- GABAJournal, genetic engineering & biotechnology · 2021Review
- Direct Structural Insights into GABATrends in biochemical sciences · 2021Review
- Substituted Cysteine Modification and Protection withMolecular pharmacology · 2021Article
- Influence of glutamate and GABA transport on brain excitatory/inhibitory balance.Experimental biology and medicine (Maywood, N.J.) · 2021Review
- Modulation of α1β3γ2 GABAProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels.Frontiers in physiology · 2021Review
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- Competitive Antagonism of Etomidate Action by Diazepam: In Vitro GABAA Receptor and In Vivo Zebrafish Studies.Anesthesiology · 2020Article
- Photoaffinity labeling identifies an intersubunit steroid-binding site in heteromeric GABA type A (GABAThe Journal of biological chemistry · 2020Article
25 more citing papers are in PubMed but not listed here.
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8 authors at 3 institutions in 2 countries.
Funding
Abstract
GABA type A receptors (GABAAR), the brain's major inhibitory neurotransmitter receptors, are the targets for many general anesthetics, including volatile anesthetics, etomidate, propofol, and barbiturates. How such structurally diverse agents can act similarly as positive allosteric modulators of GABAARs remains unclear. Previously, photoreactive etomidate analogs identified two equivalent anesthetic-binding sites in the transmembrane domain at the β(+)-α(-) subunit interfaces, which also contain the GABA-binding sites in the extracellular domain. Here, we used R-[(3)H]5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid (R-mTFD-MPAB), a potent stereospecific barbiturate anesthetic, to photolabel expressed human α1β3γ2 GABAARs. Protein microsequencing revealed that R-[(3)H]mTFD-MPAB did not photolabel the etomidate sites at the β(+)-α(-) subunit interfaces. Instead, it photolabeled sites at the α(+)-β(-) and γ(+)-β(-) subunit interfaces in the transmembrane domain. On the (+)-side, α1M3 was labeled at Ala-291 and Tyr-294 and γ2M3 at Ser-301, and on the (-)-side, β3M1 was labeled at Met-227. These residues, like those in the etomidate site, are located at subunit interfaces near the synaptic side of the transmembrane domain. The selectivity of R-etomidate for the β(+)-α(-) interface relative to the α(+)-β(-)/γ(+)-β(-) interfaces was >100-fold, whereas that of R-mTFD-MPAB for its sites was >50-fold. Each ligand could enhance photoincorporation of the other, demonstrating allosteric interactions between the sites. The structural heterogeneity of barbiturate, etomidate, and propofol derivatives is accommodated by varying selectivities for these two classes of sites. We hypothesize that binding at any of these homologous intersubunit sites is sufficient for anesthetic action and that this explains to some degree the puzzling structural heterogeneity of anesthetics.
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