Modulation by Phenolic Compounds Provides Novel Insight into the Mechanisms of TRPA1 Activation

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Transient receptor potential ankyrin 1 (TRPA1) is a cation channel activated by a large number of noxious chemicals found in many plants, foods, cosmetics, drugs and pollutants. These substances belong to different chemical classes with the specific functional groups responsible for the channel activation. Numerous TRPA1 agonists are highly reactive electrophiles, and have ability to bind and modify thiol groups in the cytosolic part of the channel. Another group of compounds contains a large number of non-electrophiles, such as menthol, clotrimazole and nicotine, which are unable to covalently modify TRPA1. Non-electrophilic agonists have extremely different chemical structures and functions, so it seems very unlikely that a single channel structure or binding pocket could accommodate direct binding of so many diverse compounds. However, one common feature of many of these species is the ability to partition into the plasma membrane, which may in turn induce mechanical perturbations. Using intracellular calcium measurements and patch-clamp recordings we found that non-electrophilic phenol derivatives activate mouse TRPA1 and that this effect is prevented by the specific channel inhibitor HC030031. The analysis of the effects of different phenol derivatives revealed a reduction of the EC50 for TRPA1 activation with increasing length of carbon side chain in positions orto, meta and para on the phenol ring. The lengthening of the carbonyl side chain correlates also with the increase in octanol/water partition coefficient and the ability of the compounds to insert into cellular membranes. In fluorescence spectroscopy and imaging experiments with the fluorophores laurdan and 1,6-diphenyl-1,3,5-hexatriene (DPH) we found that phenol derivatives modulate membrane properties. We propose that activation of TRPA1 by non-electrophilic compounds may arise from the induction of changes in membrane properties and suggest that chemosensation may result from primary mechanosensory mechanisms.