Divergent mechanisms of steroid inhibition in the human ρ1 GABA_A receptor.

ABSTRACT: ρ-type γ-aminobutyric acid-A (GABA_A) receptors are widely distributed in the retina and brain, and are potential drug targets for the treatment of visual, sleep and cognitive disorders. Endogenous neuroactive steroids including β-estradiol and pregnenolone sulfate negatively modulate the function of ρ1 GABA_A receptors, but their inhibitory mechanisms are not clear. By combining five cryo-EM structures with electrophysiology and molecular dynamics simulations, we characterize binding sites and negative modulation mechanisms of β-estradiol and pregnenolone sulfate at the human ρ1 GABA_A receptor. β-estradiol binds in a pocket at the interface between extracellular and transmembrane domains, apparently specific to the ρ subfamily, and disturbs allosteric confor

SUBMITTER: Fan C 

PROVIDER: S-EPMC11379708 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature