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Cannabidiol inhibits Nav channels through two distinct binding sites

Author

Listed:
  • Jian Huang

    (Princeton University)

  • Xiao Fan

    (Princeton University)

  • Xueqin Jin

    (Tsinghua University)

  • Sooyeon Jo

    (Harvard Medical School)

  • Hanxiong Bear Zhang

    (Harvard Medical School)

  • Akie Fujita

    (Harvard Medical School)

  • Bruce P. Bean

    (Harvard Medical School)

  • Nieng Yan

    (Princeton University
    Tsinghua University)

Abstract

Cannabidiol (CBD), a major non-psychoactive phytocannabinoid in cannabis, is an effective treatment for some forms of epilepsy and pain. At high concentrations, CBD interacts with a huge variety of proteins, but which targets are most relevant for clinical actions is still unclear. Here we show that CBD interacts with Nav1.7 channels at sub-micromolar concentrations in a state-dependent manner. Electrophysiological experiments show that CBD binds to the inactivated state of Nav1.7 channels with a dissociation constant of about 50 nM. The cryo-EM structure of CBD bound to Nav1.7 channels reveals two distinct binding sites. One is in the IV-I fenestration near the upper pore. The other binding site is directly next to the inactivated “wedged” position of the Ile/Phe/Met (IFM) motif on the short linker between repeats III and IV, which mediates fast inactivation. Consistent with producing a direct stabilization of the inactivated state, mutating residues in this binding site greatly reduced state-dependent binding of CBD. The identification of this binding site may enable design of compounds with improved properties compared to CBD itself.

Suggested Citation

  • Jian Huang & Xiao Fan & Xueqin Jin & Sooyeon Jo & Hanxiong Bear Zhang & Akie Fujita & Bruce P. Bean & Nieng Yan, 2023. "Cannabidiol inhibits Nav channels through two distinct binding sites," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39307-6
    DOI: 10.1038/s41467-023-39307-6
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    References listed on IDEAS

    as
    1. Qiurong Wu & Jian Huang & Xiao Fan & Kan Wang & Xueqin Jin & Gaoxingyu Huang & Jiaao Li & Xiaojing Pan & Nieng Yan, 2023. "Structural mapping of Nav1.7 antagonists," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Jian Payandeh & Tamer M. Gamal El-Din & Todd Scheuer & Ning Zheng & William A. Catterall, 2012. "Crystal structure of a voltage-gated sodium channel in two potentially inactivated states," Nature, Nature, vol. 486(7401), pages 135-139, June.
    3. Jian Payandeh & Todd Scheuer & Ning Zheng & William A. Catterall, 2011. "The crystal structure of a voltage-gated sodium channel," Nature, Nature, vol. 475(7356), pages 353-358, July.
    4. Xu Zhang & Wenlin Ren & Paul DeCaen & Chuangye Yan & Xiao Tao & Lin Tang & Jingjing Wang & Kazuya Hasegawa & Takashi Kumasaka & Jianhua He & Jiawei Wang & David E. Clapham & Nieng Yan, 2012. "Crystal structure of an orthologue of the NaChBac voltage-gated sodium channel," Nature, Nature, vol. 486(7401), pages 130-134, June.
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    Cited by:

    1. Demin Ma & Yueming Zheng & Xiaoxiao Li & Xiaoyu Zhou & Zhenni Yang & Yan Zhang & Long Wang & Wenbo Zhang & Jiajia Fang & Guohua Zhao & Panpan Hou & Fajun Nan & Wei Yang & Nannan Su & Zhaobing Gao & Ji, 2023. "Ligand activation mechanisms of human KCNQ2 channel," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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