Proteinase-activated receptor 2-mediated potentiation of transient receptor potential vanilloid subfamily 1 activity reveals a mechanism for proteinase-induced inflammatory pain.
Proteinase-activated receptor (PAR) 2 is expressed on a subset of primary afferent neurons and involved in inflammatory nociception. Transient receptor potential vanilloid subfamily 1 (TRPV1) is a sensory neuron-specific cation channel that responds to capsaicin, protons, or heat stimulus. Here, we show that TRPV1 is coexpressed with PAR2 but not with PAR1 or PAR3, and that TRPV1 can functionally interact with PAR2. In human embryonic kidney 293 cells expressing TRPV1 and PAR2, PAR2 agonists increased capsaicin- or proton-evoked TRPV1 currents through a PKC-dependent pathway. After application of PAR2 agonists, temperature threshold for TRPV1 activation was reduced from 42 degrees C to well below the body temperature. PAR2-mediated Fos expression in spinal cord was decreased in TRPV1-deficient mice. The functional interaction was also observed in mouse DRG neurons and proved at a behavioral level. These represent a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by PAR2 activation.
Dai
Yi
Y
Department of Anatomy and Neuroscience, Hyogo College of Medicine, Hyogo 663-8501, Japan.
Moriyama
Tomoko
T
Higashi
Tomohiro
T
Togashi
Kazuya
K
Kobayashi
Kimiko
K
Yamanaka
Hiroki
H
Tominaga
Makoto
M
Noguchi
Koichi
K
D000818:Animals; D002478:Cells, Cultured; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology; D007249:Inflammation / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010146:Pain / Q000201:enzymology / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011955:Receptors, Drug / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013696:Temperature; D014162:Transfection
D004791:Enzyme Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D011955:Receptors, Drug; D018179:Receptors, Thrombin; C105295:protease-activated receptor 3; D011493:Protein Kinase C; D010450:Endopeptidases