QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.108.054445v1 75/4/820    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Taylor-Clark, T. E. Articles by Undem, B. J. Search for Related Content PubMed PubMed Citation Articles by Taylor-Clark, T. E. Articles by Undem, B. J.

Nitrooleic Acid, an Endogenous Product of Nitrative Stress, Activates Nociceptive Sensory Nerves via the Direct Activation of TRPA1

Department of Medicine, Johns Hopkins University, Baltimore, Maryland (T.E.T.-C., W.B., B.J.U.); and Target Discovery, Respiratory and Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania (S.G.)

Transient Receptor Potential A1 (TRPA1) is a nonselective cation channel, preferentially expressed on a subset of nociceptive sensory neurons, that is activated by a variety of reactive irritants via the covalent modification of cysteine residues. Excessive 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 electrophysiology, we have shown that 9-OA-NO₂ activates human TRPA1 channels (EC₅₀, 1 µM), whereas oleic acid had no effect on TRPA1. 9-OA-NO₂ failed to activate TRPA1 in which the cysteines at positions 619, 639, and 663 and the lysine at 708 had been mutated. TRPA1 activation by 9-OA-NO₂ was not inhibited by the NO scavenger carboxy-PTIO. 9-OA-NO₂ had no effect on another nociceptive-specific ion channel, TRPV1. 9-OA-NO₂ activated a subset of mouse vagal and trigeminal sensory neurons, which also responded to the TRPA1 agonist allyl isothiocyanate and the TRPV1 agonist capsaicin. 9-OA-NO₂ failed to activate neurons derived from TRPA1(-/-) mice. The action of 9-OA-NO₂ at nociceptive nerve terminals was investigated using an ex vivo extracellular recording preparation of individual bronchopulmonary C fibers in the mouse. 9-OA-NO₂ evoked robust action potential discharge from capsaicin-sensitive fibers with slow conduction velocities (0.4-0.7 m/s), which was inhibited by the TRPA1 antagonist AP-18. These data demonstrate that nitrooleic acid, a product of nitrative stress, can induce substantial nociceptive nerve activation through the selective and direct activation of TRPA1 channels.

Received for publication December 23, 2008.

Accepted for publication January 26, 2009.

Address correspondence to: Bradley J. Undem, 5501 Hopkins Bayview Circle, Baltimore MD 21224. E-mail: bundem{at}jhmi.edu