MODULATION OF SECRETIN RELEASE BY NEUROPEPTIDES IN SECRETIN-PRODUCINGCELLS

Nerve fibers containing bombesin (BB)/gastrin-releasing polypeptide (G RP), pituitary adenylate cyclase-activating polypeptide (PACAP), vasoa ctive intestinal polypeptide (VIP), or galanin are known to innervate the mucosa of the upper small intestine. Both BB/GRP and PACAP have be en shown to elicit secretin secretion in vivo. We studied whether the above-mentioned neuropeptides can act directly on secretin-producing c ells, including the murine neuroendocrine cell line STC-1 and a secret in cell-enriched preparation isolated from rat upper small intestinal mucosa. Secretin release from both cell types was stimulated by variou s agents known to elicit secretin release and by the neuropeptides BE, GRP, and PACAP, suggesting a comparable response between the two cell preparations. The effects of neuropeptides were further studied in ST C-1 cells. BB, GRP, and PACAP stimulated secretin release time and con centration dependently. VIP also stimulated secretin release concentra tion dependently. Stimulation by BB/GRP or PACAP was accompanied by el evation of inositol-1,4,5-trisphosphate (IP3) or cAMP, respectively. T he stimulatory effect of PACAP on secretin release was synergistically enhanced by BE without any synergistic increase in IP3 or cAMP produc tion, suggesting cross talk between different signal transduction path ways downstream of the production of these two second messengers. The L-type Ca2+ channel blocker diltiazem (10 mu M) and the Ca2+ chelator EGTA (1 mM) significantly inhibited BE-stimulated secretin release by 64% and 59%, respectively, and inhibited PACAP-stimulated release by 7 5% and 55%, respectively. The protein kinase A-specific inhibitor Rp-c AMPS (100 mu M) also inhibited both BB- and PACAP-stimulated secretin release by 30% and 62%, respectively. Galanin inhibited BB- and PACAP- stimulated secretin release and production of second messengers in a c oncentration-dependent and pertussis toxin-sensitive manner. These res ults suggested that the neuropeptides BB/GRP, PACAP, VIP, and galanin can modulate secretin release in secretin-producing cells and that STC -1 cells can serve as a useful model for studying the cellular mechani sm of secretin secretion elicited by luminal secretagogues and neurope ptides.