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Structural insights into opposing actions of neurosteroids on GABAA receptors

Author

Listed:
  • Dagimhiwat H. Legesse

    (UT Southwestern Medical Center)

  • Chen Fan

    (Stockholm University)

  • Jinfeng Teng

    (University of California San Diego)

  • Yuxuan Zhuang

    (Stockholm University)

  • Rebecca J. Howard

    (Stockholm University)

  • Colleen M. Noviello

    (University of California San Diego)

  • Erik Lindahl

    (Stockholm University
    KTH Royal Institute of Technology)

  • Ryan E. Hibbs

    (UT Southwestern Medical Center
    University of California San Diego)

Abstract

γ-Aminobutyric acid type A (GABAA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABAA receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABAA receptors, but their binding sites remain debated. Here we present structures of a synaptic GABAA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40800-1
    DOI: 10.1038/s41467-023-40800-1
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    References listed on IDEAS

    as
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    2. 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.

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