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Am J Physiol Gastrointest Liver Physiol 285: G611-G620, 2003. First published May 14, 2003; doi:10.1152/ajpgi.00388.2002
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HORMONES AND SIGNALING

PAR-2 modulates pepsinogen secretion from gastric-isolated chief cells

Stefano Fiorucci,1 Eleonora Distrutti,1 Barbara Federici,1 Barbara Palazzetti,1 Monia Baldoni,1 Antonio Morelli,1 and Giuseppe Cirino2

1Dipartimento di Medicina Clinica, Patologia, Clinica di Gastroenterologia ed Endoscopia Digestiva, Università di Perugia, 06122 Perugia, Italy, and 2Dipartimento di Farmacologia Sperimentale, Universita' di Napoli, 80131 Napoli, Italy

Submitted 10 September 2002 ; accepted in final form 3 April 2003

In the present study, we investigated whether activation of protease-activated receptor type 2 (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 stimulated 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 ERK1/2 phosphorylation and activation. Exposure of chief cells to phosphotyrosine kinase inhibitors and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one, 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 vasointestinal peptide. Exposure to Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (substance P) but not to calcitonin gene-related peptide increased pepsinogen release. The neurokinin-1 receptor antagonist, N-acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester, inhibited substance P-stimulated pepsinogen secretion, whereas it 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.

substance P; trypsin; ERK1; ERK2


Address for reprint requests and other correspondence: S. Fiorucci, Clinica di Gastroenterologia ed Epatologia, Policlinico Monteluce, Via E. Dal Pozzo, 06122 Perugia, Italy (E-mail: fiorucci{at}unipg.it).






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