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Research ArticleArticle

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

Gustav Akk, Allison L. Germann, Yusuke Sugasawa, Spencer R. Pierce, Alex S. Evers and Joe Henry Steinbach
Molecular Pharmacology October 2020, 98 (4) 303-313; DOI: https://doi.org/10.1124/molpharm.120.000066
Gustav Akk
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
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Allison L. Germann
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
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Yusuke Sugasawa
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
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Spencer R. Pierce
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
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Alex S. Evers
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
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Joe Henry Steinbach
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
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Abstract

Muscimol is a psychoactive isoxazole derived from the mushroom Amanita muscaria and a potent orthosteric agonist of the GABAA receptor. The binding of [3H]muscimol has been used to evaluate the distribution of GABAA receptors in the brain, and studies of modulation of [3H]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 GABAA 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 α1β3 GABAA 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 [3H]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 [3H]muscimol binding in the presence of the potentiating steroid allopregnanolone and the inhibitory steroid pregnenolone sulfate.

Footnotes

    • Received May 11, 2020.
    • Accepted July 17, 2020.
  • This work was supported by National Institutes of Health National Institute of General Medical Sciences [Grants GM108580 and GM108799] and funds from the Taylor Family Institute for Innovative Psychiatric Research.

  • Primary laboratory of origin: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO (G.A.).

  • https://doi.org/10.1124/molpharm.120.000066.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 98 (4)
Molecular Pharmacology
Vol. 98, Issue 4
1 Oct 2020
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Research ArticleArticle

Ligand Occupancy and State Functions

Gustav Akk, Allison L. Germann, Yusuke Sugasawa, Spencer R. Pierce, Alex S. Evers and Joe Henry Steinbach
Molecular Pharmacology October 1, 2020, 98 (4) 303-313; DOI: https://doi.org/10.1124/molpharm.120.000066

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Research ArticleArticle

Ligand Occupancy and State Functions

Gustav Akk, Allison L. Germann, Yusuke Sugasawa, Spencer R. Pierce, Alex S. Evers and Joe Henry Steinbach
Molecular Pharmacology October 1, 2020, 98 (4) 303-313; DOI: https://doi.org/10.1124/molpharm.120.000066
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