Nicotine activates the chemosensory cation channel TRPA1

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.

TRP channels in neurogastroenterology: opportunities for therapeutic intervention

“…The channel contains 14-16 NH2 terminal ankyrin repeats (Story et al, 2003), an unusual structural feature that might be relevant to its proposed mechano-sensory role (Nagata et al, 2005). TRPA1 is activated by noxious cold (17 Ϯ 1°C) and is present on sensory neurons, primarily in subsets expressing TRPV1 (Story et al, 2003;Bandell et al, 2004;Nagata et al, 2005;Bautista et al, 2006;Karashima et al, 2009). Activation of TRPA1 represents, together with TRPM8 activity, the main mechanism underlying cold sensing (Dhaka et al, 2006;Wrigley et al, 2009).…”

“…Activation of TRPA1 represents, together with TRPM8 activity, the main mechanism underlying cold sensing (Dhaka et al, 2006;Wrigley et al, 2009). Chemical activators of TRPA1 include isothiocyanates (the pungent compounds in mustard oil, wasabi and horseradish), methyl salicylate (in winter green oil), cinnamaldehyde (in cinnamon), allicin and diallyl disulphide (in garlic), acrolein (an irritant in exhaust fumes and teargas), nicotine, menthol and tetrahydrocannabinol (Bandell et al, 2004;Jordt et al, 2004;Macpherson et al, 2005;Bautista et al, 2006;Karashima et al, 2007;Talavera et al, 2009). For a more detailed review, see (McMahon and Wood, 2006).…”

Sensory Effects of Menthol and Nicotine in an E-Cigarette

“…The authors of a recent study of menthol cigarettes concluded there was no consistent effect of menthol on perceived harshness and overall impact, 20 whereas a previous study indicated that menthol could either increase or decrease the perceived harshness of a cigarette depending on nicotine concentration. 8 Studies in mice 21,22 indicate that menthol can reduce the sensory irritation from constituents of cigarette smoke, including nicotine, that stimulate the pain receptor TRPA1, 23,24 which has been shown to play a role in cough. 25 However, the numerous other chemical and particulate irritants in tobacco smoke 5,26 have precluded direct measurement of the effect of menthol on the perception of nicotine irritation alone.…”

TRP Channels and Pruritus

“…Besides cold, it is also activated by various, mostly pungent and/or irritant compounds such as botanical substances like mustard oil, delta-9-tetrahydrocannabinol, eugenol, gingerol, methyl salicylate, allyl isothiocyanate, cinnamaldehyde, formalin, and nicotine [312][313][314][315]. Like TRPV1, TRPA1 is also considered as a key player of transduction of painful stimuli and a potential target of analgesic therapies [316][317][318][319].…”