Trypsin IV or Mesotrypsin and p23 Cleave Protease-activated Receptors 1 and 2 to Induce Inflammation and Hyperalgesia
Autor: | Johanna Mohlin, Morley D. Hollenberg, Graeme S. Cottrell, Silvia Amadesi, Wolfgang Knecht, Kevin Chapman, Nathalie Vergnolle, Anita Skåregärde, Anders Peterson, Nigel W. Bunnett, Karin Gedda |
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Rok vydání: | 2007 |
Předmět: |
Male
Enteropeptidase congenital hereditary and neonatal diseases and abnormalities Trypsinogen medicine.medical_treatment Receptors Proteinase-Activated Biochemistry Rats Sprague-Dawley Mice chemistry.chemical_compound Aprotinin Ganglia Spinal medicine Animals Edema Humans Receptor PAR-2 Receptor PAR-1 Trypsin Calcium Signaling Receptor Molecular Biology Pain Measurement Inflammation Mice Knockout Protease Kunitz STI protease inhibitor Nociceptors Cell Biology Molecular biology Recombinant Proteins Rats chemistry Hyperalgesia Receptors Thrombin Capsaicin medicine.symptom Trypsin Inhibitors Granulocytes medicine.drug |
Zdroj: | Journal of Biological Chemistry. 282:26089-26100 |
ISSN: | 0021-9258 |
Popis: | 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. |
Databáze: | OpenAIRE |
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