TY - JOUR
T1 - Enhancement of muscimol binding and gating by allosteric modulators of the GABAA receptor
T2 - Relating occupancy to state functions
AU - Akk, Gustav
AU - Germann, Allison L.
AU - Sugasawa, Yusuke
AU - Pierce, Spencer R.
AU - Evers, Alex S.
AU - Steinbach, Joe Henry
N1 - Funding Information:
Primary laboratory of origin: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO (G.A.). 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. https://doi.org/10.1124/molpharm.120.000066.
Publisher Copyright:
©2020 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2020/10
Y1 - 2020/10
N2 - 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 a1b3 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.
AB - 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 a1b3 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.
UR - http://www.scopus.com/inward/record.url?scp=85090178752&partnerID=8YFLogxK
U2 - 10.1124/molpharm.120.000066
DO - 10.1124/molpharm.120.000066
M3 - Article
C2 - 32723768
AN - SCOPUS:85090178752
VL - 98
SP - 303
EP - 313
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 4
ER -