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Trypsin IV or mesotrypsin and p23 cleave protease-activated receptors 1 and 2 to induce inflammation and hyperalgesia

Knecht, W., Cottrell, G. S., Amadesi, S., Mohlin, J., Skaregarde, A., Gedda, K., Peterson, A., Chapman, K., Hollenberg, M. D., Vergnolle, N. and Bunnett, N. W. (2007) Trypsin IV or mesotrypsin and p23 cleave protease-activated receptors 1 and 2 to induce inflammation and hyperalgesia. The Journal of Biological Chemistry, 282 (36). pp. 26089-26100. ISSN 1083-351X

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To link to this item DOI: 10.1074/jbc.M703840200

Abstract/Summary

Although principally produced by the pancreas to degrade dietary proteins in the intestine, trypsins are also expressed in the nervous system and in epithelial tissues, where they have diverse actions that could be mediated by protease-activated receptors (PARs). We examined the biological actions of human trypsin IV (or mesotrypsin) and rat p23, inhibitor-resistant forms of trypsin. The zymogens trypsinogen IV and pro-p23 were expressed in Escherichia coli and purified to apparent homogeneity. Enteropeptidase cleaved both zymogens, liberating active trypsin IV and p23, which were resistant to soybean trypsin inhibitor and aprotinin. Trypsin IV cleaved N-terminal fragments of PAR(1), PAR(2), and PAR(4) at sites that would expose the tethered ligand (PAR(1) = PAR(4) > PAR(2)). Trypsin IV increased [Ca(2+)](i) in transfected cells expressing human PAR(1) and PAR(2) with similar potencies (PAR(1), 0.5 microm; PAR(2), 0.6 microm). p23 also cleaved fragments of PAR(1) and PAR(2) and signaled to cells expressing these receptors. Trypsin IV and p23 increased [Ca(2+)](i) in rat dorsal root ganglion neurons that responded to capsaicin and which thus mediate neurogenic inflammation and nociception. Intraplantar injection of trypsin IV and p23 in mice induced edema and granulocyte infiltration, which were not observed in PAR (-/-)(1)(trypsin IV) and PAR (-/-)(2) (trypsin IV and p23) mice. Trypsin IV and p23 caused thermal hyperalgesia and mechanical allodynia and hyperalgesia in mice, and these effects were absent in PAR (-/-)(2) mice but maintained in PAR (-/-)(1) mice. Thus, trypsin IV and p23 are inhibitor-resistant trypsins that can cleave and activate PARs, causing PAR(1)- and PAR(2)-dependent inflammation and PAR(2)-dependent hyperalgesia.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
No Reading authors. Back catalogue items
ID Code:30266
Uncontrolled Keywords:Animals Aprotinin/chemistry *Calcium Signaling/drug effects Capsaicin/pharmacology Edema/chemically induced/genetics/metabolism/pathology Enteropeptidase/chemistry Ganglia, Spinal/metabolism/pathology Granulocytes/metabolism/pathology Humans Hyperalgesia/chemically induced/genetics/*metabolism/pathology Inflammation/chemically induced/genetics/metabolism/pathology Male Mice Mice, Knockout Nociceptors/metabolism/pathology Pain Measurement Rats Rats, Sprague-Dawley Receptor, PAR-1/deficiency/*metabolism Receptor, PAR-2/deficiency/*physiology Receptors, Proteinase-Activated/metabolism Receptors, Thrombin/metabolism Recombinant Proteins/chemistry/genetics/metabolism/pharmacology Trypsin/chemistry/genetics/*metabolism/pharmacology Trypsin Inhibitors/chemistry
Publisher:American Society for Biochemistry and Molecular Biology

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