Site-specific effects of neurosteroids on GABA_A receptor activation and desensitization.

ABSTRACT: This study examines how site-specific binding to three identified neurosteroid-binding sites in the α₁β₃ GABA_A receptor (GABA_AR) contributes to neurosteroid allosteric modulation. We found that the potentiating neurosteroid, allopregnanolone, but not its inhibitory 3β-epimer epi-allopregnanolone, binds to the canonical β₃(+)-α₁(-) intersubunit site that mediates receptor activation by neurosteroids. In contrast, both allopregnanolone and epi-allopregnanolone bind to intrasubunit sites in the β₃ subunit, promoting receptor desensitization and the α₁ subunit promoting effects that vary between neurosteroids. Two neurosteroid analogues with diazirine moieties replacing the 3-hydroxyl (KK148 and KK150) bind

SUBMITTER: Sugasawa Y 

PROVIDER: S-EPMC7532004 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature