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GABAA receptor signalling mechanisms revealed by structural pharmacology

Author

Listed:
  • Simonas Masiulis

    (Cambridge Biomedical Campus)

  • Rooma Desai

    (Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School)

  • Tomasz Uchański

    (Vrije Universiteit Brussel (VUB)
    VIB-VUB Center for Structural Biology, VIB)

  • Itziar Serna Martin

    (University of Oxford)

  • Duncan Laverty

    (Cambridge Biomedical Campus)

  • Dimple Karia

    (University of Oxford)

  • Tomas Malinauskas

    (University of Oxford)

  • Jasenko Zivanov

    (Cambridge Biomedical Campus)

  • Els Pardon

    (Vrije Universiteit Brussel (VUB)
    VIB-VUB Center for Structural Biology, VIB)

  • Abhay Kotecha

    (Thermo Fisher Scientific)

  • Jan Steyaert

    (Vrije Universiteit Brussel (VUB)
    VIB-VUB Center for Structural Biology, VIB)

  • Keith W. Miller

    (Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School)

  • A. Radu Aricescu

    (Cambridge Biomedical Campus
    University of Oxford)

Abstract

Type-A γ-aminobutyric (GABAA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABAA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABAA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABAA receptor modulators.

Suggested Citation

  • Simonas Masiulis & Rooma Desai & Tomasz Uchański & Itziar Serna Martin & Duncan Laverty & Dimple Karia & Tomas Malinauskas & Jasenko Zivanov & Els Pardon & Abhay Kotecha & Jan Steyaert & Keith W. Mill, 2019. "GABAA receptor signalling mechanisms revealed by structural pharmacology," Nature, Nature, vol. 565(7740), pages 454-459, January.
    • Handle: RePEc:nat:nature:v:565:y:2019:i:7740:d:10.1038_s41586-018-0832-5
    DOI: 10.1038/s41586-018-0832-5
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    Cited by:

    1. Heng Liu & Dapeng Sun & Alexander Myasnikov & Marjorie Damian & Jean-Louis Baneres & Ji Sun & Cheng Zhang, 2021. "Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    2. Nathan L. Absalom & Vivian W. Y. Liao & Katrine M. H. Johannesen & Elena Gardella & Julia Jacobs & Gaetan Lesca & Zeynep Gokce-Samar & Alexis Arzimanoglou & Shimriet Zeidler & Pasquale Striano & Pierr, 2022. "Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. 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.
    8. Marie S. Prevost & Nathalie Barilone & Gabrielle Dejean de la Bâtie & Stéphanie Pons & Gabriel Ayme & Patrick England & Marc Gielen & François Bontems & Gérard Pehau-Arnaudet & Uwe Maskos & Pierre , 2023. "An original potentiating mechanism revealed by the cryo-EM structures of the human α7 nicotinic receptor in complex with nanobodies," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    9. Nikhil Bharambe & Zhuowen Li & David Seiferth & Asha Manikkoth Balakrishna & Philip C. Biggin & Sandip Basak, 2024. "Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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