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Divergent mechanisms of steroid inhibition in the human ρ1 GABAA receptor

Author

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  • Chen Fan

    (KTH Royal Institute of Technology
    Stockholm University)

  • John Cowgill

    (Stockholm University)

  • Rebecca J. Howard

    (KTH Royal Institute of Technology
    Stockholm University)

  • Erik Lindahl

    (KTH Royal Institute of Technology
    Stockholm University)

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.

Suggested Citation

  • Chen Fan & John Cowgill & Rebecca J. Howard & Erik Lindahl, 2024. "Divergent mechanisms of steroid inhibition in the human ρ1 GABAA receptor," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51904-7
    DOI: 10.1038/s41467-024-51904-7
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    References listed on IDEAS

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    1. Nuriya Mukhtasimova & Won Yong Lee & Hai-Long Wang & Steven M. Sine, 2009. "Detection and trapping of intermediate states priming nicotinic receptor channel opening," Nature, Nature, vol. 459(7245), pages 451-454, May.
    2. Chang Sun & Hongtao Zhu & Sarah Clark & Eric Gouaux, 2023. "Cryo-EM structures reveal native GABAA receptor assemblies and pharmacology," Nature, Nature, vol. 622(7981), pages 195-201, October.
    3. Vikram Dalal & Mark J. Arcario & John T. Petroff & Brandon K. Tan & Noah M. Dietzen & Michael J. Rau & James A. J. Fitzpatrick & Grace Brannigan & Wayland W. L. Cheng, 2024. "Lipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    4. Dagimhiwat H. Legesse & Chen Fan & Jinfeng Teng & Yuxuan Zhuang & Rebecca J. Howard & Colleen M. Noviello & Erik Lindahl & Ryan E. Hibbs, 2023. "Structural insights into opposing actions of neurosteroids on GABAA receptors," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
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