title: A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1.
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.
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming 650223, Yunnan, China.|University of Chinese Academy of Sciences, Beijing 100009, China.
authors.forename: Shilong
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California 95616, USA.
authors.forename: Fan
authors.identifier: http://orcid.org/0000-0002-9406-7710
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Wei
authors.affiliation: College of Biological Science and Engineering, Fuzhou University, Fuzhou 350116, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Hong
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming 650223, Yunnan, China.|University of Chinese Academy of Sciences, Beijing 100009, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Li
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming 650223, Yunnan, China.|University of Chinese Academy of Sciences, Beijing 100009, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Luo
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming 650223, Yunnan, China.
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Rong
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California 95616, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California 95616, USA.
authors.forename: Jie
authors.identifier: http://orcid.org/0000-0002-4161-627X
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Neurobiology, Neuroscience Research Institute, Peking University Health Science Center, Beijing 100191, China.|Department of Molecular and Cellular Pharmacology, PKU-IDG/McGovern Institute for Brain Research, Peking University School of Pharmaceutical Sciences, Beijing 100191, China.|Department of Pharmacology, Qingdao University, Qingdao 266021, China.
authors.forename: KeWei
authors.initials: K
authors.lastname: Wang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms, Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming 650223, Yunnan, China.
authors.forename: Ren
authors.initials: R
authors.lastname: Lai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001180:Arthropod Venoms / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D001181:Arthropods / Q000235:genetics / Q000378:metabolism*; D001733:Bites and Stings / Q000235:genetics / Q000378:metabolism*; D001831:Body Temperature; D018360:Crystallography, X-Ray; D006358:Hot Temperature; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D050916:TRPV Cation Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D001180:Arthropod Venoms; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse