Gastric carcinoids (types I and II) involve the transformation of naive enterochromaffin-like
(ECL) cells to the neoplastic state and are associated primarily with hypergastrinemia.
In this study, we evaluated 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 signal transduction
pathways that mediate this effect.
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 chain reaction
(RT-PCR) with gene-specific oligonucleotide primers was performed to characterize
the PACAP/VIP receptor subtype(s).
PACAP/VIP neuropeptide-stimulated BrdU uptake was significantly greater (3.4-3.8-fold
greater than control) than that at the maximal dose of gastrin (2.2-fold greater than
control). PACAP-stimulated ECL cell proliferation (EC50, approximately 3 x 10(-)14
mol/L) was approximately 100-fold more potent than VIP (EC50, approximately 3x 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 presence 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 tyrosine kinase
as well as mitogen-activated protein kinase.
PACAP/VIP-related peptides are more potent modulators of ECL cell proliferation than
gastrin, and their effect is mediated by a PACAP-specific receptor whose activation
is transduced by multiple intracellular messenger systems.