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bioRxiv · 10.1101/2024.01.23.576874

Divergent mechanisms of steroid inhibition in the human {rho}1 GABA(A) receptor

Fan, C.·Cowgill, J.·Howard, R. J.·Lindahl, E.
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Abstract

{rho}-type {gamma}-aminobutyric acid-A (GABAA) 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 {beta}-estradiol and pregnenolone sulfate negatively modulate the function of {rho}1 GABAA receptors, but their inhibitory mechanisms are not clear. By combining four new cryo-EM structures with electrophysiology and molecular dynamics simulations, we characterize binding sites and negative modulation mechanisms of {beta}-estradiol and pregnenolone sulfate at the human {rho}1 GABAA receptor. {beta}-estradiol binds in a pocket at the interface between extracellular and transmembrane domains, apparently specific to the {rho} 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 {rho}1 inhibition by two different neuroactive steroids, with potential implications for subtype-specific gating and pharmacological design.

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Fan, C., Cowgill, J., Howard, R. J., Lindahl, E.. 2024-01-26. Divergent mechanisms of steroid inhibition in the human {rho}1 GABA(A) receptor. https://doi.org/10.1101/2024.01.23.576874

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