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Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1

DOI: 10.1186/1744-8069-4-30

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Abstract:

Our search for endogenous chemical activators utilizing a bioactive lipid library screen identified a cyclopentane PGD2 metabolite, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), as a TRPA1 agonist. Similar to CA and AITC, this electrophilic molecule is known to modify cysteines of cellular target proteins. Electophysiological recordings verified that 15d-PGJ2 specifically activates TRPA1 and not TRPV1 or TRPM8 (thermoTRPs also enriched in DRG). Accordingly, we identified a population of mouse DRG neurons responsive to 15d-PGJ2 and AITC that is absent in cultures derived from TRPA1 knockout mice. The irritant molecules that activate TRPA1 evoke nociceptive responses. However, 15d-PGJ2 has not been correlated with painful sensations; rather, it is considered to mediate anti-inflammatory processes via binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ). Our in vivo studies revealed that 15d-PGJ2 induced acute nociceptive responses when administered cutaneously. Moreover, mice deficient in the TRPA1 channel failed to exhibit such behaviors.In conclusion, we show that 15d-PGJ2 induces acute nociception when administered cutaneously and does so via a TRPA1-specific mechanism.The prostaglandins (PGs) are a class of biomolecules derived from arachidonic acid (AA) that are involved in a variety of signaling processes including inflammation. For example, PGE2 and PGI2 are produced during inflammation and contribute to the direct sensitization of nociceptive neurons of the dorsal root ganglia (DRG). Downstream of binding to its G protein-coupled receptor (GPCR), PGE2 sensitizes nociceptive neurons to thermal stimuli via PKA-dependent phosphorylation of the heat- and capsaicin-gated Transient Receptor Potential (TRP) ion channel TRPV1 [1]. TRPV1 is the founding mammalian member of a subfamily of TRP channels gated by temperature (dubbed thermoTRPs)[2].TRPA1, first characterized as a thermoTRP channel gated by noxious cold (although this finding is con

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