Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2.
Proteinase-activated receptor 2 (PAR-2) is a recently characterized G-protein coupled receptor that is cleaved and activated by pancreatic trypsin. Trypsin is usually considered a digestive enzyme in the intestinal lumen. We examined the hypothesis that trypsin, at concentrations normally present in the lumen of the small intestine, is also a signaling molecule that specifically regulates enterocytes by activating PAR-2. PAR-2 mRNA was highly expressed in the mucosa of the small intestine and in an enterocyte cell line. Immunoreactive PAR-2 was detected at the apical membrane of enterocytes, where it could be cleaved by luminal trypsin. Physiological concentrations of pancreatic trypsin and a peptide corresponding to the tethered ligand of PAR-2, which is exposed by trypsin cleavage, stimulated generation of inositol 1,4,5-trisphosphate, arachidonic acid release, and secretion of prostaglandin E2 and F1alpha from enterocytes and a transfected cell line. Application of trypsin to the apical membrane of enterocytes and to the mucosal surface of everted sacs of jejunum also stimulated prostaglandin E2 secretion. Thus, luminal trypsin activates PAR-2 at the apical membrane of enterocytes to stimulate secretion of eicosanoids, which regulate multiple cell types in a paracrine and autocrine manner. We conclude that trypsin is a signaling molecule that specifically regulates enterocytes by triggering PAR-2.
Kong
W
W
Department of Surgery, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0660, USA.
McConalogue
K
K
Khitin
L M
LM
Hollenberg
M D
MD
Payan
D G
DG
Böhm
S K
SK
Bunnett
N W
NW
D000818:Animals; D002460:Cell Line; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014357:Trypsin / Q000494:pharmacology*
D011453:Prostaglandins; D044464:Receptor, PAR-2; D011956:Receptors, Cell Surface; D014357:Trypsin