PT  - JOURNAL ARTICLE
AU  - Shaw-wen Wu
AU  - Daniel K. Fowler
AU  - Forrest J. Shaffer
AU  - Jonathon E. M. Lindberg
AU  - James Henry Peters
TI  - Ethyl vanillin activates TRPA1.
AID  - 10.1124/jpet.116.239384
DP  - 2017 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.116.239384
4099  - http://jpet.aspetjournals.org/content/early/2017/06/15/jpet.116.239384.short
4100  - http://jpet.aspetjournals.org/content/early/2017/06/15/jpet.116.239384.full
AB  - The non-selective cation channel TRPA1 is expressed in neurons of dorsal root ganglia and trigeminal ganglia and also in vagal afferent neurons that innervate the lungs and gastrointestinal tract. Many TRPA1 agonists are also reactive electrophilic compounds which form covalent adducts with TRPA1. Allyl isothiocyanate (AITC), the common reference agonist used to identify TRPA1, contains a reactive electrophilic group that covalently binds with cysteine residues of TRPA1 and confers a structural change on the channel. There is scientific motivation to identify additional compounds that can activate TRPA1 with different mechanisms of channel gating. We provide evidence that ethyl vanillin (EVA) is a TRPA1 agonist. Using fluorescent calcium imaging and whole-cell patch clamp electrophysiology on dissociated rat vagal afferent neurons and TRPA1 transfected COS-7 cells, we discovered that EVA activates cells also activated by AITC. Both agonists display similar activation profiles in terms of current density and conductance at negative voltages. Pretreatment with A967079, a selective non-competitive TRPA1 antagonist, blocks the EVA response as well as the AITC response. Furthermore, EVA does not activate any vagal afferent neurons from TRPA1 -/- mice, showing selectivity for TRPA1 in this tissue. Interestingly, EVA appears to be pharmacologically different from AITC as a TRPA1 agonist. When AITC is applied before EVA, the EVA response is occluded. These findings suggest that EVA activates TRPA1 but via a distinct mechanism that may provide greater ease for study in native systems compared to AITC and may shed light on differential modes of TRPA1 gating by ligand types.