Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain.
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.
Dai
Yi
Y
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Hyogo, Japan.
Wang
Shenglan
S
Tominaga
Makoto
M
Yamamoto
Satoshi
S
Fukuoka
Tetsuo
T
Higashi
Tomohiro
T
Kobayashi
Kimiko
K
Obata
Koichi
K
Yamanaka
Hiroki
H
Noguchi
Koichi
K
D000171:Acrolein / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017487:Ankyrins; D001522:Behavior, Animal; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004594:Electrophysiology; D004789:Enzyme Activation; D005727:Ganglia, Spinal / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017879:Isothiocyanates / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044464:Receptor, PAR-2 / Q000819:agonists / Q000378:metabolism*; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism
D017487:Ankyrins; D015220:Calcium Channels; D017879:Isothiocyanates; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D044464:Receptor, PAR-2; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C480976:Trpa1 protein, rat; D000171:Acrolein; C004471:allyl isothiocyanate; D011493:Protein Kinase C; D010738:Type C Phospholipases; C012843:cinnamaldehyde