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

Nat Commun. 2015 Sep 30;6:8297. doi: 10.1038/ncomms9297.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Arthropod Venoms / genetics
  • Arthropod Venoms / metabolism
  • Arthropod Venoms / toxicity*
  • Arthropods / genetics
  • Arthropods / metabolism*
  • Bites and Stings / genetics
  • Bites and Stings / metabolism*
  • Body Temperature
  • Crystallography, X-Ray
  • Hot Temperature
  • Humans
  • Mice
  • Molecular Sequence Data
  • Nociceptors / drug effects
  • Nociceptors / metabolism*
  • Pain / genetics
  • Pain / metabolism*
  • Sequence Alignment
  • TRPV Cation Channels / chemistry
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*

Substances

  • Arthropod Venoms
  • TRPV Cation Channels
  • TRPV1 protein, human
  • TRPV1 protein, mouse

Associated data

  • GENBANK/KM675476
  • PDB/2MVA