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Accelerated Communication

Prostaglandin-Induced Activation of Nociceptive Neurons via Direct Interaction with Transient Receptor Potential A1 (TRPA1)

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

Inflammation contributes to pain hypersensitivity through multiple mechanisms. Among the most well characterized of these is the sensitization of primary nociceptive neurons by arachidonic acid metabolites such as prostaglandins through G protein-coupled receptors. However, in light of the recent discovery that the nociceptor-specific ion channel transient receptor potential A1 (TRPA1) can be activated by exogenous electrophilic irritants through direct covalent modification, we reasoned that electrophilic carbon-containing A- and J-series prostaglandins, metabolites of prostaglandins (PG) E₂ and D₂, respectively, would excite nociceptive neurons through direct activation of TRPA1. Consistent with this prediction, the PGD₂ metabolite 15-deoxy-^12,14-prostaglandin J₂ (15dPGJ₂) activated heterologously expressed human TRPA1 (hTRPA1-HEK), as well as a subset of chemosensitive mouse trigeminal neurons. The effects of 15dPGJ₂ on neurons were blocked by both the nonselective TRP channel blocker ruthenium red and the TRPA1 inhibitor (HC-030031), but unaffected by the TRPV1 blocker iodo-resiniferatoxin. In whole-cell patch-clamp studies on hTRPA1-HEK cells, 15dPGJ₂ evoked currents similar to equimolar allyl isothiocyanate (AITC) in the nominal absence of calcium, suggesting a direct mechanism of activation. Consistent with the hypothesis that TRPA1 activation required reactive electrophilic moieties, A- and J-series prostaglandins, and the isoprostane 8-iso-prostaglandin A₂-evoked calcium influx in hTRPA1-HEK cells with similar potency and efficacy. It is noteworthy that this effect was not mimicked by their nonelectrophilic precursors, PGE₂ and PGD₂, or PGB₂, which differs from PGA₂ only in that its electrophilic carbon is rendered unreactive through steric hindrance. Taken together, these data suggest a novel mechanism through which reactive prostanoids may activate nociceptive neurons independent of prostaglandin receptors.

Address correspondence to: Dr. Bradley J. Undem, Johns Hopkins Medical Institutions, Johns Hopkins Asthma and Allergy Center, 3A.44, Baltimore, MD 21224. E-mail: bundem{at}jhmi.edu

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