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

Shilong Yang, Fan Yang, Ningning Wei, Jing Hong, Bowen Li, Lei Luo, Mingqiang Rong, Vladimir Yarov-Yarovoy, Jie Zheng (), KeWei Wang () and Ren Lai ()
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Shilong Yang: Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology
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
Lei Luo: Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology
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
Ren Lai: Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9297

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