Protease-Activated Receptor 2 Sensitizes the Capsaicin Receptor Transient Receptor Potential Vanilloid Receptor 1 to Induce Hyperalgesia
Open Access
- 5 May 2004
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 24 (18), 4300-4312
- https://doi.org/10.1523/jneurosci.5679-03.2004
Abstract
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. PAR2was coexpressed with TRPV1 in small- to medium-diameter neurons of the dorsal root ganglia (DRG), as determined by immunofluorescence. PAR2agonists increased intracellular [Ca2+] ([Ca2+]i) in these neurons in culture, and PAR2-responsive neurons also responded to the TRPV1 agonist capsaicin, confirming coexpression of PAR2and TRPV1. PAR2agonists potentiated capsaicin-induced increases in [Ca2+]iin 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+]iand TRPV1 currents. Activation of PAR2or PKC induced phosphorylation of TRPV1 in HEK cells, suggesting a direct regulation of the channel. Intraplantar injection of a PAR2agonist caused persistent thermal hyperalgesia that was prevented by antagonism or deletion of TRPV1. Coinjection of nonhyperalgesic doses of PAR2agonist and capsaicin induced hyperalgesia that was inhibited by deletion of TRPV1 or antagonism of PKC. PAR2activation 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 PAR2sensitize TRPV1 through PKC. Antagonism of PAR2, TRPV1, or PKC may abrogate protease-induced thermal hyperalgesia.Keywords
This publication has 63 references indexed in Scilit:
- Trypsin IV, a Novel Agonist of Protease-activated Receptors 2 and 4Journal of Biological Chemistry, 2004
- Stimulation of proteinase-activated receptor 2 excites jejunal afferent nerves in anaesthetised ratsThe Journal of Physiology, 2003
- Mast cell tryptase and proteinase‐activated receptor 2 induce hyperexcitability of guinea‐pig submucosal neuronsThe Journal of Physiology, 2003
- Protein Kinase Cα Is Required for Vanilloid Receptor 1 ActivationJournal of Biological Chemistry, 2002
- Agonists of proteinase‐activated receptor 1 induce plasma extravasation by a neurogenic mechanismBritish Journal of Pharmacology, 2001
- Extrapancreatic Trypsin-2 Cleaves Proteinase-Activated Receptor-2Biochemical and Biophysical Research Communications, 2000
- Impaired Nociception and Pain Sensation in Mice Lacking the Capsaicin ReceptorScience, 2000
- The Cloned Capsaicin Receptor Integrates Multiple Pain-Producing StimuliNeuron, 1998
- Protease-activated receptor 3 is a second thrombin receptor in humansNature, 1997
- Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activationCell, 1991