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Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain
Yi Dai, … , Hiroki Yamanaka, Koichi Noguchi
Yi Dai, … , Hiroki Yamanaka, Koichi Noguchi
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1979-1987. https://doi.org/10.1172/JCI30951.
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Research Article Neuroscience Article has an altmetric score of 6

Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain

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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 (PIP2) suppressed this potentiation. Decrease of plasma membrane PIP2 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 PIP2. 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

Yi Dai, Shenglan Wang, Makoto Tominaga, Satoshi Yamamoto, Tetsuo Fukuoka, Tomohiro Higashi, Kimiko Kobayashi, Koichi Obata, Hiroki Yamanaka, Koichi Noguchi

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Figure 5

SL-NH2 sensitizes TRPA1 channel in DRG neurons.

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SL-NH2 sensitizes TRPA1 channel in DRG neurons.
(A and B) Representative...
(A and B) Representative traces of TRPA1-like currents by repeated AITC (300 μM) application without (A) or with (B) SL-NH2 (100 μM) treatment. AITC was reapplied 120 seconds after exposure to SL-NH2. Capsaicin (Cap; 1 μM) was applied to identify whether it was a TRPA1 current at the end of recording. (C) Effects of intracellular PIP2 on the PAR2-mediated sensitization of TRPA1. Currents were normalized to the currents evoked initially by AITC in the absence of the SL-NH2. In some experiments, a water-soluble PIP2 (10 μM) or polylysine was added to pipette solution. The potentiation by SL-NH2 was inhibited when the PIP2 was added to pipette solution. In contrast, intracellular application of polylysine (p-lysine; 3 μg/ml), a PIP2 scavenger, potentiated AITC-activated currents in DRG neurons. *P < 0.05, **P < 0.0005, versus control; #P < 0.05 versus SL-NH2; unpaired Student’s t test. (D) Effects of intracellular PIP2 on AITC-induced current density in DRG neurons. PIP2 or polylysine was added in the pipette solutions. *P < 0.05 versus control; unpaired Student’s t test. Numbers in parentheses indicate cells tested.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 7 patents
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