Species differences and molecular determinant of TRPA1 cold sensitivity

Nat Commun. 2013;4:2501. doi: 10.1038/ncomms3501.


TRPA1 is an ion channel and has been proposed as a thermosensor across species. In invertebrate and ancestral vertebrates such as fly, mosquito, frog, lizard and snakes, TRPA1 serves as a heat receptor, a sensory input utilized for heat avoidance or infrared detection. However, in mammals, whether TRPA1 is a receptor for noxious cold is highly controversial, as channel activation by cold was observed by some groups but disputed by others. Here we attribute the discrepancy to species differences. We show that cold activates rat and mouse TRPA1 but not human or rhesus monkey TRPA1. At the molecular level, a single residue within the S5 transmembrane domain (G878 in rodent but V875 in primate) accounts for the observed difference in cold sensitivity. This residue difference also underlies the species-specific effects of menthol. Together, our findings identify the species-specific cold activation of TRPA1 and reveal a molecular determinant of cold-sensitive gating.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution*
  • Animals
  • Calcium Channels / genetics
  • Calcium Channels / metabolism*
  • Cold Temperature
  • Differential Threshold / physiology*
  • Evoked Potentials, Somatosensory / drug effects
  • Evoked Potentials, Somatosensory / physiology
  • Humans
  • Ion Channel Gating
  • Isothiocyanates / pharmacology
  • Macaca mulatta / physiology
  • Menthol / pharmacology
  • Mice
  • Molecular Sequence Data
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Olfactory Perception / drug effects
  • Patch-Clamp Techniques
  • Protein Structure, Tertiary
  • Rats
  • Sequence Homology, Amino Acid
  • Species Specificity
  • TRPA1 Cation Channel
  • TRPC Cation Channels / genetics
  • TRPC Cation Channels / metabolism*
  • Transient Receptor Potential Channels / genetics
  • Transient Receptor Potential Channels / metabolism*


  • Calcium Channels
  • Isothiocyanates
  • Nerve Tissue Proteins
  • TRPA1 Cation Channel
  • TRPA1 protein, human
  • TRPC Cation Channels
  • Transient Receptor Potential Channels
  • Trpa1 protein, mouse
  • Trpa1 protein, rat
  • acetyl isothiocyanate
  • Menthol