Nitrooleic Acid, an Endogenous Product of Nitrative Stress, Activates Nociceptive Sensory Nerves via the Direct Activation

Transient Receptor Potential A1 (TRPA1) is a nonselective cat-ion channel, preferentially expressed on a subset of nociceptive sensory neurons, that is activated by a variety of reactive irri-tants via the covalent modification of cysteine residues. Exces-sive nitric oxide during inflammation (nitrative stress), leads to the nitration of phospholipids, resulting in the formation of highly reactive cysteine modifying agents, such as nitrooleic acid (9-OA-NO2). Using calcium imaging and electrophysiol-ogy, we have shown that 9-OA-NO2 activates human TRPA1 channels (EC50, 1 M), whereas oleic acid had no effect on TRPA1. 9-OA-NO2 failed to activate TRPA1 in which the cys-teines at positions 619, 639, and 663 and the lysine at 708 had been mutated. TRPA1 activation by 9-OA-NO2 was not inhib-ited by the NO scavenger carboxy-PTIO. 9-OA-NO2 had n