Submitted on September 10, 2002
Accepted on April 3, 2003
PAR-2 Modulates Pespinogen Secretion from Gastric Isolated Chief Cells
Stefano Fiorucci1*, Eleonora Distrutti1, Barbara Federici1, Barbara Palazzetti1, Monia Baldoni1, Antonio Morelli1, and Giuseppe Cirino2
1 Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, Universita di Perugia, Perugia, Italy
2 Dipartimento di Farmacologia Sperimantale, Universita di Napoli, Naples, Italy
* To whom correspondence should be addressed. E-mail: fiorucci{at}unipg.it.
In the present study we have investigated whether activation of type 2 of protease activated receptor (PAR)-2 with SLIGRL (SL)-NH2, a short mimetic agonistic peptide directly stimulates pepsinogen secretion from gastric isolated pepsinogen-secreting (chief) cells. Immunostaining of gastric dispersed chief cells with a specific anti-PAR-2 antibody demonstrated expression of PAR-2 receptors on membrane and cytoplasm. SL-NH2, and trypsin, potently stimulates pepsinogen secretion (EC50= 0.3 nM) and caused Ca2+ mobilization (EC50=0. 6 nM). In contrast to SL-NH2, the scramble peptide LSIGRL-NH2 failed to stimulate pepsinogen release. Exposure to SL-NH2 also resulted in extracellular signal-regulated kinases (ERK)-1 and -2 phosphorylation and activation. Exposure of chief cells to phosphotyrosine kinase inhibitors and PD98059, a selective MEK inhibitor, significantly reduced secretion induced by SL-NH2. Pepsinogen secretion induced by SL-NH2 was desensitized by pretreating the cells with the mimetic peptide and trypsin and exposure to SL-NH2 abrogates pepsinogen secretion induced by carbachol and CCK-8, but not secretion induced by secretin and VIP. Exposure to Substance P (SP), but not to calcitonin gene related peptide, increased pepsinogen release. The NK1 receptor antagonist, L-732,138 inhibited SP-stimulated pepsinogen secretion while did not affect secretion induced by SL-NH2. Collectively, these data indicate that PAR-2 is expressed on gastric chief cells and that its activation causes a Ca2+-ERK dependent stimulation of pepsinogen secretion.
