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Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain.
J Clin Invest. 2007 Jul; 117(7):1979-87.JCI

Abstract

Proinflammatory agents trypsin and mast cell tryptase cleave and activate PAR2, which is expressed on sensory nerves to cause neurogenic inflammation. Transient receptor potential A1 (TRPA1) is an excitatory ion channel on primary sensory nerves of pain pathway. Here, we show that a functional interaction of PAR2 and TRPA1 in dorsal root ganglion (DRG) neurons could contribute to the sensation of inflammatory pain. Frequent colocalization of TRPA1 with PAR2 was found in rat DRG neurons. PAR2 activation increased the TRPA1 currents evoked by its agonists in HEK293 cells transfected with TRPA1, as well as DRG neurons. Application of phospholipase C (PLC) inhibitors or phosphatidylinositol-4,5-bisphosphate (PIP(2)) suppressed this potentiation. Decrease of plasma membrane PIP(2) levels through antibody sequestration or PLC-mediated hydrolysis mimicked the potentiating effects of PAR2 activation at the cellular level. Thus, the increased TRPA1 sensitivity may have been due to activation of PLC, which releases the inhibition of TRPA1 from plasma membrane PIP(2). These results identify for the first time to our knowledge a sensitization mechanism of TRPA1 and a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by TRPA1 activation.

Authors+Show Affiliations

Department of Anatomy and Neuroscience, Hyogo College of Medicine, Hyogo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17571167

Citation

Dai, Yi, et al. "Sensitization of TRPA1 By PAR2 Contributes to the Sensation of Inflammatory Pain." The Journal of Clinical Investigation, vol. 117, no. 7, 2007, pp. 1979-87.
Dai Y, Wang S, Tominaga M, et al. Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J Clin Invest. 2007;117(7):1979-87.
Dai, Y., Wang, S., Tominaga, M., Yamamoto, S., Fukuoka, T., Higashi, T., Kobayashi, K., Obata, K., Yamanaka, H., & Noguchi, K. (2007). Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. The Journal of Clinical Investigation, 117(7), 1979-87.
Dai Y, et al. Sensitization of TRPA1 By PAR2 Contributes to the Sensation of Inflammatory Pain. J Clin Invest. 2007;117(7):1979-87. PubMed PMID: 17571167.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. AU - Dai,Yi, AU - Wang,Shenglan, AU - Tominaga,Makoto, AU - Yamamoto,Satoshi, AU - Fukuoka,Tetsuo, AU - Higashi,Tomohiro, AU - Kobayashi,Kimiko, AU - Obata,Koichi, AU - Yamanaka,Hiroki, AU - Noguchi,Koichi, PY - 2006/11/14/received PY - 2007/04/10/accepted PY - 2007/6/16/pubmed PY - 2007/9/19/medline PY - 2007/6/16/entrez SP - 1979 EP - 87 JF - The Journal of clinical investigation JO - J Clin Invest VL - 117 IS - 7 N2 - Proinflammatory agents trypsin and mast cell tryptase cleave and activate PAR2, which is expressed on sensory nerves to cause neurogenic inflammation. Transient receptor potential A1 (TRPA1) is an excitatory ion channel on primary sensory nerves of pain pathway. Here, we show that a functional interaction of PAR2 and TRPA1 in dorsal root ganglion (DRG) neurons could contribute to the sensation of inflammatory pain. Frequent colocalization of TRPA1 with PAR2 was found in rat DRG neurons. PAR2 activation increased the TRPA1 currents evoked by its agonists in HEK293 cells transfected with TRPA1, as well as DRG neurons. Application of phospholipase C (PLC) inhibitors or phosphatidylinositol-4,5-bisphosphate (PIP(2)) suppressed this potentiation. Decrease of plasma membrane PIP(2) levels through antibody sequestration or PLC-mediated hydrolysis mimicked the potentiating effects of PAR2 activation at the cellular level. Thus, the increased TRPA1 sensitivity may have been due to activation of PLC, which releases the inhibition of TRPA1 from plasma membrane PIP(2). These results identify for the first time to our knowledge a sensitization mechanism of TRPA1 and a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by TRPA1 activation. SN - 0021-9738 UR - https://www.unboundmedicine.com/medline/citation/17571167/Sensitization_of_TRPA1_by_PAR2_contributes_to_the_sensation_of_inflammatory_pain_ L2 - https://doi.org/10.1172/JCI30951 DB - PRIME DP - Unbound Medicine ER -