1. Divergent mechanisms of steroid inhibition in the human ρ1 GABAA receptor.
- Author
-
Fan, Chen, Cowgill, John, Howard, Rebecca J., and Lindahl, Erik
- Subjects
TRANSMEMBRANE domains ,MOLECULAR structure ,MOLECULAR dynamics ,PREGNENOLONE ,BINDING sites ,ION channels - 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 GABAA 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 GABAA receptor. β-estradiol binds in a pocket at the interface between extracellular and transmembrane domains, apparently specific to the ρ subfamily, and disturbs allosteric conformational transitions linking GABA binding to pore opening. In contrast, pregnenolone sulfate binds inside the pore to block ion permeation, with a preference for activated structures. These results illuminate contrasting mechanisms of ρ1 inhibition by two different neuroactive steroids, with potential implications for subtype-specific gating and pharmacological design. Neurological processes from vision to cognition rely on precise control of ion channels, particularly GABAA receptors. Here, the authors report structures of a ρ1 GABAA receptor with naturally occurring steroids, revealing their specific interactions and suggesting approaches to understand and develop drugs. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF