Nicotine is a highly addictive substance that activates nicotinic acetylcholine receptors (nAChRs), which are a class of ligand-activated cation channels defined by this ligand. Smoking-cessation therapies include topical application of nicotine, but patient usage may be limited partly due to local discomfort and irritation associated with the patches. Talavera et al. show that high concentrations of nicotine, like those in smoking-cessation treatments, activated the transient receptor potential (TRP) family member TRPA1, which is a calcium-conducting cation channel found in nociceptive neurons and which mediates responses to painful cold and irritating chemicals such as mustard oil. Chinese hamster ovary (CHO) cells expressing mouse TRPA1 exhibited a delayed current in response to extracellularly applied nicotine. Nicotine activated TRPA1 channels in cell-free inside-out patches, and this was faster than the activation in intact cells, suggesting that part of the delayed response may be due to nicotine’s diffusion across the plasma membrane to reach its binding site in the channel. Nicotine stimulated calcium transients in a subset of mouse trigeminal ganglion neurons, and the proportion of responding neurons was diminished in Trpa1-knockout mice. Application of nicotine to the noses of wild-type, but not Trpa1-knockout, mice triggered airway constriction, and this was blocked by the addition of menthol, a chemical that is added to cigarettes to produce a cooling, soothing, analgesic effect. Menthol also reversed nicotine-induced current and calcium transients in the TRPA1-expressing CHO cells. Thus, TRPA1 appears to be a previously unrecognized receptor for nicotine, which likely contributes to the irritating effects of high concentrations of nicotine.
K. Talavera, M. Gees, Y. Karashima, V. M. Meseguer, J. A. J. Vanoirbeek, N. Damann, W. Everaerts, M. Benoit, A. Janssens, R. Vennekens, F. Viana, B. Nemery, B. Nilius, T. Voets, Nicotine activates the chemosensory cation channel TRPA1. Nat. Neurosci. 12, 1293–1299 (2009). [PubMed]