+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia

Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia

Journal of Neuroscience 24(18): 4300-4312

Inflammatory proteases (mast cell tryptase and trypsins) cleave protease-activated receptor 2 (PAR2) on spinal afferent neurons and cause persistent inflammation and hyperalgesia by unknown mechanisms. We determined whether transient receptor potential vanilloid receptor 1 (TRPV1), a cation channel activated by capsaicin, protons, and noxious heat, mediates PAR2-induced hyperalgesia. PAR2 was coexpressed with TRPV1 in small- to medium-diameter neurons of the dorsal root ganglia (DRG), as determined by immunofluorescence. PAR2 agonists increased intracellular [Ca2+] ([Ca2+]i) in these neurons in culture, and PAR2-responsive neurons also responded to the TRPV1 agonist capsaicin, confirming coexpression of PAR2 and TRPV1. PAR2 agonists potentiated capsaicin-induced increases in [Ca2+]i in TRPV1-transfected human embryonic kidney (HEK) cells and DRG neurons and potentiated capsaicin-induced currents in DRG neurons. Inhibitors of phospholipase C and protein kinase C (PKC) suppressed PAR2-induced sensitization of TRPV1-mediated changes in [Ca2+]i and TRPV1 currents. Activation of PAR2 or PKC induced phosphorylation of TRPV1 in HEK cells, suggesting a direct regulation of the channel. Intraplantar injection of a PAR2 agonist caused persistent thermal hyperalgesia that was prevented by antagonism or deletion of TRPV1. Coinjection of nonhyperalgesic doses of PAR2 agonist and capsaicin induced hyperalgesia that was inhibited by deletion of TRPV1 or antagonism of PKC. PAR2 activation also potentiated capsaicin-induced release of substance P and calcitonin gene-related peptide from superfused segments of the dorsal horn of the spinal cord, where they mediate hyperalgesia. We have identified a novel mechanism by which proteases that activate PAR2 sensitize TRPV1 through PKC. Antagonism of PAR2, TRPV1, or PKC may abrogate protease-induced thermal hyperalgesia.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 012460686

Download citation: RISBibTeXText

PMID: 15128844

DOI: 10.1523/jneurosci.5679-03.2004

Related references

Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. Journal of Physiology 578(Pt 3): 715-733, 2006

T1456 Histamine and Serotonin Sensitizes the Transient Receptor Potential Vanilloid Receptor 4 to Induce Visceral Allodynia and Hyperalgesia. Gastroenterology 134(4): A-559-A-560, 2008

Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain. Neuroscience 193: 440-451, 2012

T1429 Protease Activated Receptor 2 Sensitizes Transient Receptor Potential Vanilloid 4 On Mouse Colonic Dorsal Root Ganglia Neurons. Gastroenterology 134(4): A-554, 2008

Transient receptor potential vanilloid 4 mediates protease activated receptor 2-induced sensitization of colonic afferent nerves and visceral hyperalgesia. American Journal of Physiology. Gastrointestinal and Liver Physiology 294(5): G1288-G1298, 2008

S1798 Protease-Activated Receptor 2 (Par2) Directly Activates Transient Receptor Potential (Trp) Vanilloid 1 and 4 Channels to Induce Neurogenic Inflammation. Gastroenterology 138(5): S-276-S-277, 2010

Protein kinase C phosphorylation sensitizes but does not activate the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1). Proceedings of the National Academy of Sciences of the United States of America 100(21): 12480-5, 2003

Su1077 - Mucosally Expressed Protease-Activated Receptor 2 and Transient Receptor Potential Vanilloid 1 are Associated with Functional Heartburn. Gastroenterology 154(6): S-478, 2018

Protease-Activated Receptor-2 Up-Regulates Transient Receptor Potential Vanilloid 4 Function in Mouse Esophageal Keratinocyte. Digestive Diseases and Sciences 60(12): 3570-3578, 2016

Dietary capsaicin prevents nonalcoholic fatty liver disease through transient receptor potential vanilloid 1-mediated peroxisome proliferator-activated receptor δ activation. Pflugers Archiv 465(9): 1303-1316, 2014

Involvement of transient receptor potential vanilloid 1 receptors in protease-activated receptor-2-induced joint inflammation and nociception. European Journal of Pain 14(4): 351-358, 2010

17beta-estradiol activates estrogen receptor beta-signalling and inhibits transient receptor potential vanilloid receptor 1 activation by capsaicin in adult rat nociceptor neurons. Endocrinology 149(11): 5540-5548, 2008

Protease Activated Receptor 2 (PAR2) Induces Long-Term Depression in the Hippocampus through Transient Receptor Potential Vanilloid 4 (TRPV4). Frontiers in Molecular Neuroscience 10: 42, 2017

Neutrophil Elastase Activates Protease-activated Receptor-2 (PAR2) and Transient Receptor Potential Vanilloid 4 (TRPV4) to Cause Inflammation and Pain. Journal of Biological Chemistry 290(22): 13875-13887, 2015

Protease-activated receptor 2-mediated protection of myocardial ischemia-reperfusion injury: role of transient receptor potential vanilloid receptors. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 297(6): R1681-R1690, 2009