RT Journal Article
SR Electronic
T1 Analysis of Modulation of the <em>ρ</em>1 GABA<sub>A</sub> Receptor by Combinations of Inhibitory and Potentiating Neurosteroids Reveals Shared and Distinct Binding Sites
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 280
OP 291
DO 10.1124/mol.120.119842
VO 98
IS 4
A1 Allison L. Germann
A1 David E. Reichert
A1 Ariel B. Burbridge
A1 Spencer R. Pierce
A1 Alex S. Evers
A1 Joe Henry Steinbach
A1 Gustav Akk
YR 2020
UL http://molpharm.aspetjournals.org/content/98/4/280.abstract
AB The ρ1 GABAA receptor is prominently expressed in the retina and is present at lower levels in several brain regions and other tissues. Although the ρ1 receptor is insensitive to many anesthetic drugs that modulate the heteromeric GABAA receptor, it maintains a rich and multifaceted steroid pharmacology. The receptor is negatively modulated by 5β-reduced steroids, sulfated or carboxylated steroids, and β-estradiol, whereas many 5α-reduced steroids potentiate the receptor. In this study, we analyzed modulation of the human ρ1 GABAA receptor by several neurosteroids, individually and in combination, in the framework of the coagonist concerted transition model. Experiments involving coapplication of two or more steroids revealed that the receptor contains at least three classes of distinct, nonoverlapping sites for steroids, one each for the inhibitory steroids pregnanolone (3α5βP), 3α5βP sulfate, and β-estradiol. The site for 3α5βP can accommodate the potentiating steroid 5αTHDOC. The findings are discussed with respect to receptor modulation by combinations of endogenous neurosteroids.SIGNIFICANCE STATEMENT The study describes modulation of the ρ1 GABAA receptor by neurosteroids. The coagonist concerted transition model was used to determine overlap of binding sites for several inhibitory and potentiating steroids.