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Molecular Pharmacology

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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 Joseph Henry Steinbach
Molecular Pharmacology July 28, 2020, MOLPHARM-AR-2020-000066; DOI: https://doi.org/10.1124/molpharm.120.000066
Gustav Akk
1Anesthesiology, Washington University School of Medicine, United States
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  • For correspondence: akk@morpheus.wustl.edu
Allison L. Germann
1Anesthesiology, Washington University School of Medicine, United States
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Yusuke Sugasawa
1Anesthesiology, Washington University School of Medicine, United States
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Spencer R. Pierce
1Anesthesiology, Washington University School of Medicine, United States
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Alex S. Evers
2Anesthesiology and Pharmacology, Washington University School of Medicine, United States of America
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Joseph Henry Steinbach
3Dept. of Anesthesiology, Washington University School of Medicine, United States of America
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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.

  • Func. analysis receptor/ion channel mutants
  • GABA receptors
  • GABAA, GABAC
  • Ligand-gated ion channels
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 99 (3)
Molecular Pharmacology
Vol. 99, Issue 3
1 Mar 2021
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OtherArticle

Ligand occupancy and state functions

Gustav Akk, Allison L. Germann, Yusuke Sugasawa, Spencer R. Pierce, Alex S. Evers and Joseph Henry Steinbach
Molecular Pharmacology July 28, 2020, MOLPHARM-AR-2020-000066; DOI: https://doi.org/10.1124/molpharm.120.000066

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OtherArticle

Ligand occupancy and state functions

Gustav Akk, Allison L. Germann, Yusuke Sugasawa, Spencer R. Pierce, Alex S. Evers and Joseph Henry Steinbach
Molecular Pharmacology July 28, 2020, MOLPHARM-AR-2020-000066; DOI: https://doi.org/10.1124/molpharm.120.000066
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