PACAP AND VIP STIMULATE ENZYME-SECRETION IN RAT PANCREATIC ACINI VIA INTERACTION WITH VIP PACAP-2 RECEPTORS - ADDITIVE AUGMENTATION OF CCK CARBACHOL-INDUCED ENZYME-RELEASE

The binding and biological effect of pituitary adenylate cyclase activ ating polypeptide (PACAP), a novel hypothalamic peptide with high sequ ence homology to vasoactive intestinal polypeptide (VIP), were studied in rat AR 4-2 J pancreatic carcinoma cells and isolated rat pancreati c acini. PACAP(1-27) and analogue PACAP(1-23,VIP-24-28), but not VIP, displaced potently and reversibly I-125-PACAP(1-27) from binding to an abundantly expressed high affinity PACAP-preferring receptor on AR 4- 2 J cells, referred to as ''PACAP-1 receptor.'' High affinity binding was dependent on N-terminal and C-terminal residues of PACAP(1-27): PA CAP(1-24,Cys-25) (7.3 +/- 1.6 muM), PACAP(1-23) (8.2 +/- 1.5 muM), VIP (>30 muM), PACAP(3-27), PACAP(1-19), PACAP(3-19), PACAP(1-12), and PA CAP(18-38) (all >50 muM) showed low or no binding potency. In contrast , high and low affinity binding of I-125-VIP to AR 4-2 J cells was dis placed equipotently by PACAP(1-27) and VIP, thus defining on these cel ls, in addition, two scarcely expressed binding sites, designated ''VI P/PACAP-2 receptor,'' similar or identical to the previously described high and low affinity acinar VIP receptor. Binding of I-125-PACAP(I-2 7) to a high and low affinity binding site on rat pancreatic acini was inhibited equipotently by PACAP(1-27) and VIP, identifying these site s as VIP/PACAP-2 receptors. PACAP(1-23) recognized both type 2 binding sites with only slightly lower affinity. PACAP(1-27), PACAP(1-38), PA CAP(1-23,VIP-24-28), and PACAP(1-23) equipotently stimulated acinar li pase release and cyclic AMP production in pancreatic acini. Co-incubat ion of PACAP(1-27) or VIP with cholecystokinin-8 or carbachol revealed additive effects on enzyme secretion. Our results suggest the predomi nant expression of VIP/PACAP-2 receptors on rat pancreatic acini, wher eas AR 4-2 J cells express mainly PACAP-1 receptors. PACAP is a potent ligand for both receptor types and has to be regarded as a novel VIP- like pancreatic secretagogue.