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The desensitization gate of inhibitory Cys-loop receptors

Author

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  • Marc Gielen

    (Physiology & Pharmacology, University College London
    Present address: Institut Pasteur, Channel-Receptor Unit, 25 rue du Docteur Roux, 75724 Paris, France)

  • Philip Thomas

    (Physiology & Pharmacology, University College London)

  • Trevor G. Smart

    (Physiology & Pharmacology, University College London)

Abstract

Cys-loop neurotransmitter-gated ion channels are vital for communication throughout the nervous system. Following activation, these receptors enter into a desensitized state in which the ion channel shuts even though the neurotransmitter molecules remain bound. To date, the molecular determinants underlying this most fundamental property of Cys-loop receptors have remained elusive. Here we present a generic mechanism for the desensitization of Cys-loop GABAA (GABAARs) and glycine receptors (GlyRs), which both mediate fast inhibitory synaptic transmission. Desensitization is regulated by interactions between the second and third transmembrane segments, which affect the ion channel lumen near its intracellular end. The GABAAR and GlyR pore blocker picrotoxin prevented desensitization, consistent with its deep channel-binding site overlapping a physical desensitization gate.

Suggested Citation

  • Marc Gielen & Philip Thomas & Trevor G. Smart, 2015. "The desensitization gate of inhibitory Cys-loop receptors," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7829
    DOI: 10.1038/ncomms7829
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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. Xiaofen Liu & Weiwei Wang, 2023. "Asymmetric gating of a human hetero-pentameric glycine receptor," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. Eric Gibbs & Emily Klemm & David Seiferth & Arvind Kumar & Serban L. Ilca & Philip C. Biggin & Sudha Chakrapani, 2023. "Conformational transitions and allosteric modulation in a heteromeric glycine receptor," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. 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.
    5. 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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