Pituitary adenylate cyclase-activating polypeptide modulates gastric enterochromaffin-like cell proliferation in rats

Background & Aims: Gastric carcinoids (types I and II) involve the transfor mation of naive enterochromarffin-like (ECL) cells to the neoplastic state and are associated primarily with hypergastrinemia. In this study, we evalu ated the effects of two related neuropeptides, pituitary adenylate cyclase- activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP), on ECL cell proliferation and characterized the receptor subtype(s) and si gnal transduction pathways that mediate this effect. Methods: Purified rat ECL cells were analyzed in culture for DNA synthesis as measured by 24-hour 5-bromo-2-deoxyuridine (BrdU) uptake. Reverse-transcription polymerase cha in reaction (RT-PCR) with gene-specific oligonucleotide primers was perform ed to characterize the PACAP/VIP receptor subtype(s). Results: PACAP/VIP ne uropeptide-stimulated BrdU uptake was significantly greater (3.4-3.8-fold g reater than control) than that at the maximal dose of gastrin (2.2-fold gre ater than control). PACAP-stimulated ECL cell proliferation (EC50, similar to 3 x 10(-14) mol/L) was similar to 100-fold more potent than VIP (EC50, s imilar to 3 x 10(-12) mol/L). The stimulated BrdU uptake by both PACAP and VIP was competitively inhibited by PACAP-receptor antagonist (IC50, 10(-9) mol/L, 3 x 10(-9) mol/L, respectively) and VIP-receptor antagonist (IC50, 3 x 10(-7) mol/L, 5 x 10(-7) mol/L, respectively). RT-PCR identified the pre sence of the PACAP-specific but not PACAP/VIP receptor subtypes. The PACAP- stimulated BrdU uptake was inhibited (70%-80%) by inhibitors of adenosine 3 ',5'-cyclic monophosphate, phosphatidylinositol 3 kinase, and protein tyros ine kinase as well as mitogen-activated protein kinase. Conclusions: PACAP/ VIP-related peptides are more potent modulators of ECL cell proliferation t han gastrin, and their effect is mediated by a PACAP-specific receptor whos e activation is transduced by multiple intracellular messenger systems.