ArticleThe Journal of biological chemistry2015
Positive and Negative Allosteric Modulation of an α1β3γ2 γ-Aminobutyric Acid Type A (GABAA) Receptor by Binding to a Site in the Transmembrane Domain at the γ+-β- Interface.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 30 citations in OpenAlex.
- Spiro Hydantoins Can Reverse the Action of Positive Allosteric Modulators on GABAACS medicinal chemistry letters · 2025Article
- Novel Spiro-Barbiturates Can Reverse the Action of General Anesthetics on the GABAJournal of medicinal chemistry · 2025Article
- β subunits of GABACommunications biology · 2022Article
- Selective actions of benzodiazepines at the transmembrane anaesthetic binding sites of the GABABritish journal of pharmacology · 2021Article
- Photoaffinity labeling identifies an intersubunit steroid-binding site in heteromeric GABA type A (GABAThe Journal of biological chemistry · 2020Article
- Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery.Trends in pharmacological sciences · 2019Review
- Identifying Drugs that Bind Selectively to Intersubunit General Anesthetic Sites in theMolecular pharmacology · 2019Article
- Monod-Wyman-Changeux Allosteric Shift Analysis in MutantMolecular pharmacology · 2019Article
- Cryo-EM structure of the human α1β3γ2 GABANature · 2019Article
- Etomidate Effects on Desensitization and Deactivation ofThe Journal of pharmacology and experimental therapeutics · 2019Article
- Comparison of αβδ and αβγ GABAPharmacological research · 2018Review
- Competitive Antagonism of Anesthetic Action at the γ-Aminobutyric Acid Type A Receptor by a Novel Etomidate Analog with Low Intrinsic Efficacy.Anesthesiology · 2017Article
- Enantiomeric barbiturates bind distinct inter- and intrasubunit binding sites in a nicotinic acetylcholine receptor (nAChR).The Journal of biological chemistry · 2017Article
- General Anesthetic Binding Sites in Human α4β3δ γ-Aminobutyric Acid Type A Receptors (GABAARs).The Journal of biological chemistry · 2016Article
- Tryptophan and Cysteine Mutations in M1 Helices of α1β3γ2L γ-Aminobutyric Acid Type A Receptors Indicate Distinct Intersubunit Sites for Four Intravenous Anesthetics and One Orphan Site.Anesthesiology · 2016Article
- Mapping General Anesthetic Sites in Heteromeric γ-Aminobutyric Acid Type A Receptors Reveals a Potential For Targeting Receptor Subtypes.Anesthesia and analgesia · 2016Review
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- A half century of γ-aminobutyric acid.Brain and neuroscience advancesReview
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
In the process of developing safer general anesthetics, isomers of anesthetic ethers and barbiturates have been discovered that act as convulsants and inhibitors of γ-aminobutyric acid type A receptors (GABAARs) rather than potentiators. It is unknown whether these convulsants act as negative allosteric modulators by binding to the intersubunit anesthetic-binding sites in the GABAAR transmembrane domain (Chiara, D. C., Jayakar, S. S., Zhou, X., Zhang, X., Savechenkov, P. Y., Bruzik, K. S., Miller, K. W., and Cohen, J. B. (2013) J. Biol. Chem. 288, 19343-19357) or to known convulsant sites in the ion channel or extracellular domains. Here, we show that S-1-methyl-5-propyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid (S-mTFD-MPPB), a photoreactive analog of the convulsant barbiturate S-MPPB, inhibits α1β3γ2 but potentiates α1β3 GABAAR responses. In the α1β3γ2 GABAAR, S-mTFD-MPPB binds in the transmembrane domain with high affinity to the γ(+)-β(-) subunit interface site with negative energetic coupling to GABA binding in the extracellular domain at the β(+)-α(-) subunit interfaces. GABA inhibits S-[(3)H]mTFD-MPPB photolabeling of γ2Ser-280 (γM2-15') in this site. In contrast, within the same site GABA enhances photolabeling of β3Met-227 in βM1 by an anesthetic barbiturate, R-[(3)H]methyl-5-allyl-5-(m-trifluoromethyl-diazirynylphenyl)barbituric acid (mTFD-MPAB), which differs from S-mTFD-MPPB in structure only by chirality and two hydrogens (propyl versus allyl). S-mTFD-MPPB and R-mTFD-MPAB are predicted to bind in different orientations at the γ(+)-β(-) site, based upon the distance in GABAAR homology models between γ2Ser-280 and β3Met-227. These results provide an explanation for S-mTFD-MPPB inhibition of α1β3γ2 GABAAR function and provide a first demonstration that an intersubunit-binding site in the GABAAR transmembrane domain binds negative and positive allosteric modulators.
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Registered trials
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.