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Enhancement of Muscimol Binding and Gating by Allosteric Modulators of the GABA A Receptor: Relating Occupancy to State Functions.

التفاصيل البيبلوغرافية
العنوان: Enhancement of Muscimol Binding and Gating by Allosteric Modulators of the GABA A Receptor: Relating Occupancy to State Functions.
المؤلفون: Akk G; Department of Anesthesiology (G.A., A.L.G., Y.S., S.R.P., A.S.E., J.H.S.) and the Taylor Family Institute for Innovative Psychiatric Research (G.A., A.S.E., J.H.S.), Washington University School of Medicine, St. Louis, Missouri akk@morpheus.wustl.edu., Germann AL; Department of Anesthesiology (G.A., A.L.G., Y.S., S.R.P., A.S.E., J.H.S.) and the Taylor Family Institute for Innovative Psychiatric Research (G.A., A.S.E., J.H.S.), Washington University School of Medicine, St. Louis, Missouri., Sugasawa Y; Department of Anesthesiology (G.A., A.L.G., Y.S., S.R.P., A.S.E., J.H.S.) and the Taylor Family Institute for Innovative Psychiatric Research (G.A., A.S.E., J.H.S.), Washington University School of Medicine, St. Louis, Missouri., Pierce SR; Department of Anesthesiology (G.A., A.L.G., Y.S., S.R.P., A.S.E., J.H.S.) and the Taylor Family Institute for Innovative Psychiatric Research (G.A., A.S.E., J.H.S.), Washington University School of Medicine, St. Louis, Missouri., Evers AS; Department of Anesthesiology (G.A., A.L.G., Y.S., S.R.P., A.S.E., J.H.S.) and the Taylor Family Institute for Innovative Psychiatric Research (G.A., A.S.E., J.H.S.), Washington University School of Medicine, St. Louis, Missouri., Steinbach JH; Department of Anesthesiology (G.A., A.L.G., Y.S., S.R.P., A.S.E., J.H.S.) and the Taylor Family Institute for Innovative Psychiatric Research (G.A., A.S.E., J.H.S.), Washington University School of Medicine, St. Louis, Missouri.
المصدر: Molecular pharmacology [Mol Pharmacol] 2020 Oct; Vol. 98 (4), pp. 303-313.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics
مواضيع طبية MeSH: GABA-A Receptor Agonists/*pharmacology , Muscimol/*pharmacology , Receptors, GABA-A/*metabolism , Steroids/*pharmacology, Allosteric Regulation/drug effects ; Binding Sites ; HEK293 Cells ; Humans ; Multiprotein Complexes/chemistry ; Multiprotein Complexes/genetics ; Muscimol/chemistry ; Pregnanolone/pharmacology ; Pregnenolone/pharmacology ; Receptors, GABA-A/chemistry ; Receptors, GABA-A/genetics ; Recombinant Proteins/chemistry ; Recombinant Proteins/metabolism ; Tritium/chemistry
مستخلص: Muscimol is a psychoactive isoxazole derived from the mushroom Amanita muscaria and a potent orthosteric agonist of the GABA A receptor. The binding of [ 3 H]muscimol has been used to evaluate the distribution of GABA A receptors in the brain, and studies of modulation of [ 3 H]muscimol binding by allosteric GABAergic modulators such as barbiturates and steroid anesthetics have provided insight into the modes of action of these drugs on the GABA A receptor. It has, however, not been feasible to directly apply interaction parameters derived from functional studies to describe the binding of muscimol to the receptor. Here, we employed the Monod-Wyman-Changeux concerted transition model to analyze muscimol binding isotherms. We show that the binding isotherms from recombinant α 1 β 3 GABA A receptors can be qualitatively predicted using electrophysiological data pertaining to properties of receptor activation and desensitization in the presence of muscimol. The model predicts enhancement of [ 3 H]muscimol binding in the presence of the steroids allopregnanolone and pregnenolone sulfate, although the steroids interact with distinct sites and either enhance (allopregnanolone) or reduce (pregnenolone sulfate) receptor function. We infer that the concerted transition model can be used to link radioligand binding and electrophysiological data. SIGNIFICANCE STATEMENT: The study employs a three-state resting-active-desensitized model to link radioligand binding and electrophysiological data. We show that the binding isotherms can be qualitatively predicted using parameters estimated in electrophysiological experiments and that the model accurately predicts the enhancement of [ 3 H]muscimol binding in the presence of the potentiating steroid allopregnanolone and the inhibitory steroid pregnenolone sulfate.
(Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)
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معلومات مُعتمدة: R01 GM108580 United States GM NIGMS NIH HHS; R01 GM108799 United States GM NIGMS NIH HHS
المشرفين على المادة: 0 (GABA-A Receptor Agonists)
0 (GABRA1 protein, human)
0 (GABRB3 protein, human)
0 (Multiprotein Complexes)
0 (Receptors, GABA-A)
0 (Recombinant Proteins)
0 (Steroids)
04Y4D91RG0 (pregnenolone sulfate)
10028-17-8 (Tritium)
2763-96-4 (Muscimol)
73R90F7MQ8 (Pregnenolone)
BXO86P3XXW (Pregnanolone)
تواريخ الأحداث: Date Created: 20200903 Date Completed: 20201106 Latest Revision: 20240229
رمز التحديث: 20240229
مُعرف محوري في PubMed: PMC7472144
DOI: 10.1124/molpharm.120.000066
PMID: 32873746
قاعدة البيانات: MEDLINE
الوصف
تدمد:1521-0111
DOI:10.1124/molpharm.120.000066