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Biotech / Medical : ACADIA Pharmaceuticals Inc (ACAD) -- Ignore unavailable to you. Want to Upgrade?

To: scaram(o)uche who wrote (106)	2/17/2005 4:43:32 PM
From: tuck	Read Replies (1) \| Respond to of 588

[PAR-2: downregulation by C-CBL by ubiquitination, etc.] "C-CBL mediates ubiquitination, degradation and down-regulation of human protease-activated receptor 2 (PAR2)" jbc.org Full text freebie. >> Nat Med. 2001 Jul;7(7):821-6. Comment in: Nat Med. 2001 Jul;7(7):772-3. Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, Cirino G, Gerard N, Basbaum AI, Andrade-Gordon P, Hollenberg MD, Wallace JL. Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada. Using a combined pharmacological and gene-deletion approach, we have delineated a novel mechanism of neurokinin-1 (NK-1) receptor-dependent hyperalgesia induced by proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor expressed on nociceptive primary afferent neurons. Injections into the paw of sub-inflammatory doses of PAR2 agonists in rats and mice induced a prolonged thermal and mechanical hyperalgesia and elevated spinal Fos protein expression. This hyperalgesia was markedly diminished or absent in mice lacking the NK-1 receptor, preprotachykinin-A or PAR2 genes, or in rats treated with a centrally acting cyclooxygenase inhibitor or treated by spinal cord injection of NK-1 antagonists. Here we identify a previously unrecognized nociceptive pathway with important therapeutic implications, and our results point to a direct role for proteinases and their receptors in pain transmission.<< >>Nat Med. 2000 Feb;6(2):151-8. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL, Caughey GH, Mitchell SE, Williams LM, Geppetti P, Mayer EA, Bunnett NW. Department of Surgery and Physiology, University of California, San Francisco, CA 94143, USA. Trypsin and mast cell tryptase cleave proteinase-activated receptor 2 and, by unknown mechanisms, induce widespread inflammation. We found that a large proportion of primary spinal afferent neurons, which express proteinase-activated receptor 2, also contain the proinflammatory neuropeptides calcitonin gene-related peptide and substance P. Trypsin and tryptase directly signal to neurons to stimulate release of these neuropeptides, which mediate inflammatory edema induced by agonists of proteinase-activated receptor 2. This new mechanism of protease-induced neurogenic inflammation may contribute to the proinflammatory effects of mast cells in human disease. Thus, tryptase inhibitors and antagonists of proteinase-activated receptor 2 may be useful anti-inflammatory agents.<< Cheers, Tuck