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α subunits in GABAA receptors are dispensable for GABA and diazepam action
Open accessAbstract
The major isoform of the GABA A receptor is α 1 β 2 γ 2 . The binding sites for the agonist GABA are located at the β 2 +/α 1 − subunit interfaces and the modulatory site for benzodiazepines at α 1 +/γ 2 −. In the absence of α 1 subunits, a receptor was formed that was gated by GABA and modulated by diazepam similarly. This indicates that alternative subunits can take over the role of the α 1 subunits. Point mutations were introduced in β 2 or γ 2 subunits at positions homologous to α 1 − benzodiazepine binding and GABA binding positions, respectively. From this mutation work we conclude that the site for GABA is located at a β 2 +/β 2 − subunit interface and that the diazepam site is located at the β 2 +/γ 2 − subunit interface. Computational docking leads to a structural hypothesis attributing this non-canonical interaction to a binding mode nearly identical with the one at the α 1 +/γ 2 − interface. Thus, the β 2 subunit can take over the role of the α 1 subunit for the formation of both sites, its minus side for the GABA binding site and its plus side for the diazepam binding site.
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“GABA-gated currents increase hyperbolically with increasing diazepam concentrations in cellular models (Berezhnoy et al., 2008; Wongsamitkul et al., 2017), including recombinant human GABA-A receptors (Atack, 2009) (Figure 3a).”
From Pharmacological principles for safe benzodiazepine and Z-drug dose reduction (2026) · cites this paper as Wongsamitkul et al., 2017
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Metadata
- Authors
- Wongsamitkul, N., Maldifassi, M. C., Simeone, X., Baur, R., Ernst, M., & Sigel, E.
- Affiliations
- University of Bern (CH)
- Medical University of Vienna (AT)
- Corresponding author
- Sigel, Erwin
- Venue
- Scientific Reports
- Published
- 2017-11-14
- Volume
- 7
- Issue
- 1
- Pages
- 15498-15498
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5686171
- OpenAlex
- W2767629627
- Cited by
- 51
- References
- 46
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 7 · 2023: 6 · 2022: 13 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 6
- FWCI
- 1.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- BORIS (University Library Bern) (submittedVersion, cc-by)
- Open Access CRIS of the University of Bern
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (315230, 315230_156929/1, 156929)
- Austrian Science Fund (P 27746)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- GABAA receptor, alpha1 subunit, beta2 subunit, gamma2 subunit, GABA binding sites, benzodiazepine modulation, point mutations, ligand binding sites, receptor gating, computational docking
- MeSH terms
- Animals, Binding Sites, Diazepam, gamma-Aminobutyric Acid, Oocytes, Receptors, GABA-A, Xenopus, Mutagenesis, Site-Directed, Point Mutation, Protein Isoforms, Protein Subunits, Structural Homology, Protein, Molecular Docking Simulation
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