LUMINAL TRYPSIN MAY REGULATE ENTEROCYTES THROUGH PROTEINASE-ACTIVATEDRECEPTOR-2

Proteinase-activated receptor 2 (PAR-2) is a recently characterized G- protein coupled receptor that is cleaved and activated by pancreatic t rypsin. Trypsin is usually considered a digestive enzyme in the intest inal lumen, We examined the hypothesis that trypsin, at concentrations normally present in the lumen of the small intestine, is also a signa ling molecule that specifically regulates enterocytes by activating PA R-2, PAR-2 mRNA was highly expressed in the mucosa of the small intest ine and in an enterocyte cell line, Immunoreactive PAR-2 was detected at the apical membrane of enterocytes, where it could be cleaved by lu minal trypsin. Physiological concentrations of pancreatic trypsin and a peptide corresponding to the tethered ligand of PAR-2, which is expo sed by trypsin cleavage, stimulated generation of inositol 1,4,5-trisp hosphate, arachidonic acid release, and secretion of prostaglandin E-2 and F-1 alpha from enterocytes and a transfected cell line. Applicati on of trypsin to the apical membrane of enterocytes and to the mucosal surface of everted sacs of jejunum also stimulated prostaglandin E-2 secretion, Thus, luminal trypsin activates PAR-2 at the apical membran e of enterocytes to stimulate secretion of eicosanoids, which regulate multiple cell types in a paracrine and autocrine manner, We conclude Chat trypsin is a signaling molecule that specifically regulates enter ocytes by triggering PAR-2.