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A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1

Author

Listed:
  • Shilong Yang

    (Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology
    University of Chinese Academy of Sciences)

  • Fan Yang

    (University of California)

  • Ningning Wei

    (Neuroscience Research Institute, Peking University Health Science Center)

  • Jing Hong

    (College of Biological Science and Engineering, Fuzhou University)

  • Bowen Li

    (Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology
    University of Chinese Academy of Sciences)

  • Lei Luo

    (Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology
    University of Chinese Academy of Sciences)

  • Mingqiang Rong

    (Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology)

  • Vladimir Yarov-Yarovoy

    (University of California)

  • Jie Zheng

    (University of California)

  • KeWei Wang

    (Neuroscience Research Institute, Peking University Health Science Center
    PKU-IDG/McGovern Institute for Brain Research, Peking University School of Pharmaceutical Sciences
    Qingdao University)

  • Ren Lai

    (Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology)

Abstract

The capsaicin receptor TRPV1 ion channel is a polymodal nociceptor that responds to heat with exquisite sensitivity through an unknown mechanism. Here we report the identification of a novel toxin, RhTx, from the venom of the Chinese red-headed centipede that potently activates TRPV1 to produce excruciating pain. RhTx is a 27-amino-acid small peptide that forms a compact polarized molecule with very rapid binding kinetics and high affinity for TRPV1. We show that RhTx targets the channel’s heat activation machinery to cause powerful heat activation at body temperature. The RhTx–TRPV1 interaction is mediated by the toxin’s highly charged C terminus, which associates tightly to the charge-rich outer pore region of the channel where it can directly interact with the pore helix and turret. These findings demonstrate that RhTx binding to the outer pore can induce TRPV1 heat activation, therefore providing crucial new structural information on the heat activation machinery.

Suggested Citation

  • Shilong Yang & Fan Yang & Ningning Wei & Jing Hong & Bowen Li & Lei Luo & Mingqiang Rong & Vladimir Yarov-Yarovoy & Jie Zheng & KeWei Wang & Ren Lai, 2015. "A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9297
    DOI: 10.1038/ncomms9297
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    Cited by:

    1. Heng Zhang & Jia-Jia Lin & Ya-Kai Xie & Xiu-Zu Song & Jia-Yi Sun & Bei-Lei Zhang & Yun-Kun Qi & Zhen-Zhong Xu & Fan Yang, 2023. "Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Maxim V Nikolaev & Natalia A Dorofeeva & Margarita S Komarova & Yuliya V Korolkova & Yaroslav A Andreev & Irina V Mosharova & Eugene V Grishin & Denis B Tikhonov & Sergey A Kozlov, 2017. "TRPV1 activation power can switch an action mode for its polypeptide ligands," PLOS ONE, Public Library of Science, vol. 12(5), pages 1-16, May.

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