Divergent mechanisms of steroid inhibition in the human ρ1 GABAA receptor

Chen Fan, John Cowgill, Rebecca J. Howard () and Erik Lindahl ()
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Chen Fan: KTH Royal Institute of Technology
John Cowgill: Stockholm University
Rebecca J. Howard: KTH Royal Institute of Technology
Erik Lindahl: KTH Royal Institute of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract ρ-type γ-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 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.

Date: 2024
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DOI: 10.1038/s41467-024-51904-7

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