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Structure of a human synaptic GABAA receptor

Author

Listed:
  • Shaotong Zhu

    (University of Texas Southwestern Medical Center)

  • Colleen M. Noviello

    (University of Texas Southwestern Medical Center)

  • Jinfeng Teng

    (University of Texas Southwestern Medical Center)

  • Richard M. Walsh

    (University of Texas Southwestern Medical Center)

  • Jeong Joo Kim

    (University of Texas Southwestern Medical Center)

  • Ryan E. Hibbs

    (University of Texas Southwestern Medical Center)

Abstract

Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABAA receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABAA receptor is also a prolific target for therapeutic, illicit and recreational drugs, including benzodiazepines, barbiturates, anaesthetics and ethanol. Here we present high-resolution cryo-electron microscopy structures of the human α1β2γ2 GABAA receptor, the predominant isoform in the adult brain, in complex with GABA and the benzodiazepine site antagonist flumazenil, the first-line clinical treatment for benzodiazepine overdose. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptor. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.

Suggested Citation

  • Shaotong Zhu & Colleen M. Noviello & Jinfeng Teng & Richard M. Walsh & Jeong Joo Kim & Ryan E. Hibbs, 2018. "Structure of a human synaptic GABAA receptor," Nature, Nature, vol. 559(7712), pages 67-72, July.
    • Handle: RePEc:nat:nature:v:559:y:2018:i:7712:d:10.1038_s41586-018-0255-3
    DOI: 10.1038/s41586-018-0255-3
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    Citations

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    Cited by:

    1. 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.
    2. Yingfeng Tao & Xiaoliu Zhou & Leqiang Sun & Da Lin & Huaiyuan Cai & Xi Chen & Wei Zhou & Bing Yang & Zhe Hu & Jing Yu & Jing Zhang & Xiaoqing Yang & Fang Yang & Bang Shen & Wenbao Qi & Zhenfang Fu & J, 2023. "Highly efficient and robust π-FISH rainbow for multiplexed in situ detection of diverse biomolecules," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. 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.
    4. 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.
    5. 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.
    6. 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.
    7. Emma Rie Olander & Dieter Janzen & Carmen Villmann & Anders A Jensen, 2020. "Comparison of biophysical properties of α1β2 and α3β2 GABAA receptors in whole-cell patch-clamp electrophysiological recordings," PLOS ONE, Public Library of Science, vol. 15(6), pages 1-13, June.

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