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Prostaglandin-induced activation of nociceptive neurons via direct interaction with transient receptor potential A1 (TRPA1).
Mol Pharmacol. 2008 Feb; 73(2):274-81.MP

Abstract

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) E(2) and D(2), respectively, would excite nociceptive neurons through direct activation of TRPA1. Consistent with this prediction, the PGD(2) metabolite 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) activated heterologously expressed human TRPA1 (hTRPA1-HEK), as well as a subset of chemosensitive mouse trigeminal neurons. The effects of 15dPGJ(2) 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, 15dPGJ(2) 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 A(2)-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, PGE(2) and PGD(2), or PGB(2), which differs from PGA(2) 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.

Authors+Show Affiliations

Johns Hopkins Medical Institutions, Johns Hopkins Asthma and Allergy Center, 3A.44, Baltimore, MD 21224, USA. bundem@jhmi.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18000030

Citation

Taylor-Clark, Thomas E., et al. "Prostaglandin-induced Activation of Nociceptive Neurons Via Direct Interaction With Transient Receptor Potential A1 (TRPA1)." Molecular Pharmacology, vol. 73, no. 2, 2008, pp. 274-81.
Taylor-Clark TE, Undem BJ, Macglashan DW, et al. Prostaglandin-induced activation of nociceptive neurons via direct interaction with transient receptor potential A1 (TRPA1). Mol Pharmacol. 2008;73(2):274-81.
Taylor-Clark, T. E., Undem, B. J., Macglashan, D. W., Ghatta, S., Carr, M. J., & McAlexander, M. A. (2008). Prostaglandin-induced activation of nociceptive neurons via direct interaction with transient receptor potential A1 (TRPA1). Molecular Pharmacology, 73(2), 274-81.
Taylor-Clark TE, et al. Prostaglandin-induced Activation of Nociceptive Neurons Via Direct Interaction With Transient Receptor Potential A1 (TRPA1). Mol Pharmacol. 2008;73(2):274-81. PubMed PMID: 18000030.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prostaglandin-induced activation of nociceptive neurons via direct interaction with transient receptor potential A1 (TRPA1). AU - Taylor-Clark,Thomas E, AU - Undem,Bradley J, AU - Macglashan,Donald W,Jr AU - Ghatta,Srinivas, AU - Carr,Michael J, AU - McAlexander,M Allen, Y1 - 2007/11/13/ PY - 2007/11/15/pubmed PY - 2008/2/20/medline PY - 2007/11/15/entrez SP - 274 EP - 81 JF - Molecular pharmacology JO - Mol Pharmacol VL - 73 IS - 2 N2 - 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) E(2) and D(2), respectively, would excite nociceptive neurons through direct activation of TRPA1. Consistent with this prediction, the PGD(2) metabolite 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) activated heterologously expressed human TRPA1 (hTRPA1-HEK), as well as a subset of chemosensitive mouse trigeminal neurons. The effects of 15dPGJ(2) 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, 15dPGJ(2) 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 A(2)-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, PGE(2) and PGD(2), or PGB(2), which differs from PGA(2) 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. SN - 1521-0111 UR - https://www.unboundmedicine.com/medline/citation/18000030/Prostaglandin_induced_activation_of_nociceptive_neurons_via_direct_interaction_with_transient_receptor_potential_A1__TRPA1__ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18000030 DB - PRIME DP - Unbound Medicine ER -