TY - JOUR
T1 - Analysis of modulation of the r1 GABAA receptor by combinations of inhibitory and potentiating neurosteroids reveals shared and distinct binding sites
AU - Germann, Allison L.
AU - Reichert, David E.
AU - Burbridge, Ariel B.
AU - Pierce, Spencer R.
AU - Evers, Alex S.
AU - Steinbach, Joe Henry
AU - Akk, Gustav
N1 - Funding Information:
Primary laboratory of origin (for G.K.): Washington University School of Medicine, St. Louis, MO. This work was supported by National Institutes of Health National Institute of General Medical Sciences [Grant R01 GM108580] and [Grant R01 GM108799] and funds from the Taylor Family Institute for Innovative Psychiatric Research. https://doi.org/10.1124/mol.120.119842. s This article has supplemental material available at molpharm. aspetjournals.org.
Publisher Copyright:
© 2020 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2020/10
Y1 - 2020/10
N2 - The r1 GABAA receptor is prominently expressed in the retina and is present at lower levels in several brain regions and other tissues. Although the r1 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 5b-reduced steroids, sulfated or carboxylated steroids, and b-estradiol, whereas many 5a-reduced steroids potentiate the receptor. In this study, we analyzed modulation of the human r1 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 (3a5bP), 3a5bP sulfate, and b-estradiol. The site for 3a5bP can accommodate the potentiating steroid 5aTHDOC. The findings are discussed with respect to receptor modulation by combinations of endogenous neurosteroids.
AB - The r1 GABAA receptor is prominently expressed in the retina and is present at lower levels in several brain regions and other tissues. Although the r1 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 5b-reduced steroids, sulfated or carboxylated steroids, and b-estradiol, whereas many 5a-reduced steroids potentiate the receptor. In this study, we analyzed modulation of the human r1 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 (3a5bP), 3a5bP sulfate, and b-estradiol. The site for 3a5bP can accommodate the potentiating steroid 5aTHDOC. The findings are discussed with respect to receptor modulation by combinations of endogenous neurosteroids.
UR - http://www.scopus.com/inward/record.url?scp=85090250903&partnerID=8YFLogxK
U2 - 10.1124/mol.120.119842
DO - 10.1124/mol.120.119842
M3 - Article
C2 - 32675382
AN - SCOPUS:85090250903
VL - 98
SP - 280
EP - 291
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 4
ER -