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Shared structural mechanisms of general anaesthetics and benzodiazepines

Author

Listed:
  • Jeong Joo Kim

    (University of Texas Southwestern Medical Center)

  • Anant Gharpure

    (University of Texas Southwestern Medical Center)

  • Jinfeng Teng

    (University of Texas Southwestern Medical Center)

  • Yuxuan Zhuang

    (Stockholm University)

  • Rebecca J. Howard

    (Stockholm University)

  • Shaotong Zhu

    (University of Texas Southwestern Medical Center)

  • Colleen M. Noviello

    (University of Texas Southwestern Medical Center)

  • Richard M. Walsh

    (Harvard Medical School)

  • Erik Lindahl

    (Stockholm University
    KTH Royal Institute of Technology)

  • Ryan E. Hibbs

    (University of Texas Southwestern Medical Center)

Abstract

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABAA) receptors to dampen neuronal activity in the brain1–5. However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABAA receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABAA receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABAA receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.

Suggested Citation

  • Jeong Joo Kim & Anant Gharpure & Jinfeng Teng & Yuxuan Zhuang & Rebecca J. Howard & Shaotong Zhu & Colleen M. Noviello & Richard M. Walsh & Erik Lindahl & Ryan E. Hibbs, 2020. "Shared structural mechanisms of general anaesthetics and benzodiazepines," Nature, Nature, vol. 585(7824), pages 303-308, September.
    • Handle: RePEc:nat:nature:v:585:y:2020:i:7824:d:10.1038_s41586-020-2654-5
    DOI: 10.1038/s41586-020-2654-5
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    Citations

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    Cited by:

    1. Arvind Kumar & Kayla Kindig & Shanlin Rao & Afroditi-Maria Zaki & Sandip Basak & Mark S. P. Sansom & Philip C. Biggin & Sudha Chakrapani, 2022. "Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Weronika Chojnacka & Jinfeng Teng & Jeong Joo Kim & Anders A. Jensen & Ryan E. Hibbs, 2024. "Structural insights into GABAA receptor potentiation by Quaalude," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Umang Goswami & Md Mahfuzur Rahman & Jinfeng Teng & Ryan E. Hibbs, 2023. "Structural interplay of anesthetics and paralytics on muscle nicotinic receptors," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. 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.
    5. 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.
    6. Shaotong Zhu & Akshay Sridhar & Jinfeng Teng & Rebecca J. Howard & Erik Lindahl & Ryan E. Hibbs, 2022. "Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Mackenzie J. Thompson & Farid Mansoub Bekarkhanechi & Anna Ananchenko & Hugues Nury & John E. Baenziger, 2024. "A release of local subunit conformational heterogeneity underlies gating in a muscle nicotinic acetylcholine receptor," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. John T. Petroff & Noah M. Dietzen & Ezry Santiago-McRae & Brett Deng & Maya S. Washington & Lawrence J. Chen & K. Trent Moreland & Zengqin Deng & Michael Rau & James A. J. Fitzpatrick & Peng Yuan & Th, 2022. "Open-channel structure of a pentameric ligand-gated ion channel reveals a mechanism of leaflet-specific phospholipid modulation," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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