PACAP/VIP receptors in pancreatic beta-cells: their roles in insulin secretion

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide belonging to the vasoactive intestinal polypeptide (VIP)/glucagon/secretin family. We have isolated a third PACAP receptor subtype, designated PACAPR-3, by molecular cloning. The cDNA encoding PACAPR-3 has been isolated from a mouse insulin-secreting beta-cell line MIN6 cDNA library. Mouse PACAPR-3 is a protein of 437 amino acids that has 50% and 51% identity with rat PACAP type I and type II receptors, respectively. We have expressed PACAPR-3 in mammalian cells and Xenopus oocytes. PACAPR-3 binds to VIP as well as PACAP-38 and -27, with a slightly higher affinity for PACAP-38, and is positively coupled to adenylate cyclase. PACAP-38, -27, and VIP evoked Ca2+ activated-Cl- currents in Xenopus oocytes. RNA blotting studies reveal that PACAPR-3 mRNA is expressed widely in tissues and cell lines, including pancreatic islets, insulin-secreting cell lines (MIN6, HIT-T15, and RINm5F), lung, brain, stomach, colon, and heart. Furthermore, insulin secretion from the MIN6 cells is stimulated significantly by PACAP-38 and VIP. The possible mechanisms of insulin secretion by PACAP and VIP are also discussed.