Transient Receptor Potential A1 Is a Sensory Receptor for Multiple Products of Oxidative Stress

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Abstract
Transient receptor potential A1 (TRPA1) is expressed in a subset of nociceptive sensory neurons where it acts as a sensor for environmental irritants, including acrolein, and some pungent plant ingredients such as allyl isothiocyanate and cinnamaldehyde. These exogenous compounds activate TRPA1 by covalent modification of cysteine residues. We have used electrophysiological methods and measurements of intracellular calcium concentration ([Ca2+]i) to show that TRPA1 is activated by several classes of endogenous thiol-reactive molecules. TRPA1 was activated by hydrogen peroxide (H2O2; EC50, 230 μm), by endogenously occurring alkenyl aldehydes (EC50: 4-hydroxynonenal 19.9 μm, 4-oxo-nonenal 1.9 μm, 4-hydroxyhexenal 38.9 μm) and by the cyclopentenone prostaglandin, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2, EC50: 5.6 μm). The effect of H2O2 was reversed by treatment with dithiothreitol indicating that H2O2 acts by promoting the formation of disulfide bonds whereas the actions of the alkenyl aldehydes and 15d-PGJ2 were not reversed, suggesting that these agents form Michael adducts. H2O2 and the naturally occurring alkenyl aldehydes and 15d-PGJ2 acted on a subset of isolated rat and mouse sensory neurons [∼25% of rat dorsal root ganglion (DRG) and ∼50% of nodose ganglion neurons] to evoke a depolarizing inward current and an increase in [Ca2+]i in TRPA1 expressing neurons. The abilities of H2O2, alkenyl aldehydes and 15d-PGJ2 to raise [Ca2+]i in mouse DRG neurons were greatly reduced in neurons from trpa1−/− mice. Furthermore, intraplantar injection of either H2O2 or 15d-PGJ2 evoked a nocifensive/pain response in wild-type mice, but not in trpa1−/− mice. These data demonstrate that multiple agents produced during episodes of oxidative stress can activate TRPA1 expressed in sensory neurons.