Article abstract
Nature Neuroscience 12, 1293 - 1299 (2009)
Published online: 13 September 2009 | doi:10.1038/nn.2379
Nicotine activates the chemosensory cation channel TRPA1
Karel Talavera1, Maarten Gees1, Yuji Karashima1, Víctor M Meseguer2, Jeroen A J Vanoirbeek3, Nils Damann1,5, Wouter Everaerts1,4, Melissa Benoit1, Annelies Janssens1, Rudi Vennekens1, Félix Viana2, Benoit Nemery3, Bernd Nilius1 & Thomas Voets1
Abstract
Topical application of nicotine, as used in nicotine replacement therapies, causes irritation of the mucosa and skin. This reaction has been attributed to activation of nicotinic acetylcholine receptors (nAChRs) in chemosensory neurons. In contrast with this view, we found that the chemosensory cation channel transient receptor potential A1 (TRPA1) is crucially involved in nicotine-induced irritation. We found that micromolar concentrations of nicotine activated heterologously expressed mouse and human TRPA1. Nicotine acted in a membrane-delimited manner, stabilizing the open state(s) and destabilizing the closed state(s) of the channel. In the presence of the general nAChR blocker hexamethonium, nociceptive neurons showed nicotine-induced responses that were strongly reduced in TRPA1-deficient mice. Finally, TRPA1 mediated the mouse airway constriction reflex to nasal instillation of nicotine. The identification of TRPA1 as a nicotine target suggests that existing models of nicotine-induced irritation should be revised and may facilitate the development of smoking cessation therapies with less adverse effects.
- Laboratory for Ion Channel Research, Department of Molecular Cell Biology, KU Leuven, Leuven, Belgium.
- Instituto de Neurociencias de Alicante, Universidad Miguel Hernández–Consejo Superior de Investigaciones Científicas, San Juan de Alicante, Spain.
- Laboratory of Lung Toxicology, KU Leuven, Leuven, Belgium.
- Laboratory of Experimental Urology, Department of Surgery, KU Leuven, Leuven, Belgium.
- Present address: Molecular Pharmacology, Grünenthal GmbH, Aachen, Germany.
Correspondence to: Karel Talavera1 e-mail: karel.talavera@med.kuleuven.be
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