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Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs

Author

Listed:
  • Arvind Kumar

    (Case Western Reserve University)

  • Kayla Kindig

    (Case Western Reserve University)

  • Shanlin Rao

    (University of Oxford)

  • Afroditi-Maria Zaki

    (University of Oxford)

  • Sandip Basak

    (Case Western Reserve University)

  • Mark S. P. Sansom

    (University of Oxford)

  • Philip C. Biggin

    (University of Oxford)

  • Sudha Chakrapani

    (Case Western Reserve University
    Case Western Reserve University
    Case Western Reserve University)

Abstract

Nociception and motor coordination are critically governed by glycine receptor (GlyR) function at inhibitory synapses. Consequentially, GlyRs are attractive targets in the management of chronic pain and in the treatment of several neurological disorders. High-resolution mechanistic details of GlyR function and its modulation are just emerging. While it has been known that cannabinoids such as Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent in marijuana, potentiate GlyR in the therapeutically relevant concentration range, the molecular mechanism underlying this effect is still not understood. Here, we present Cryo-EM structures of full-length GlyR reconstituted into lipid nanodisc in complex with THC under varying concentrations of glycine. The GlyR-THC complexes are captured in multiple conformational states that reveal the basis for THC-mediated potentiation, manifested as different extents of opening at the level of the channel pore. Taken together, these structural findings, combined with molecular dynamics simulations and functional analysis, provide insights into the potential THC binding site and the allosteric coupling to the channel pore.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32594-5
    DOI: 10.1038/s41467-022-32594-5
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    1. Alessio Bartocci & Andrea Grazzi & Nour Awad & Pierre-Jean Corringer & Paulo C. T. Souza & Marco Cecchini, 2024. "A millisecond coarse-grained simulation approach to decipher allosteric cannabinoid binding at the glycine receptor α1," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. 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.

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