Molecular and functional characterization of pituitary adenylate cyclase-activating polypeptide (PACAP-38)/vasoactive intestinal polypeptide receptors in pancreatic beta-cells and effects of PACAP-38 on components of the insulin secretory system

It has been previously demonstrated that pituitary adenylate cyclase-activa ting polypeptide (PACAP) regulates insulin secretion. PACAP exerts its biol ogical action by binding to at least three different receptor subtypes coup led to different signal transduction mechanisms. The signaling pathways und erlying the insulinotropic effect of PACAP involve mainly the activation of adenylate cyclase to form cAMP, which directly and indirectly, through inc reased intracellular Ca+2, stimulates insulin exocytosis. In the present st udy we have characterized the functional and molecular expression of PACAP/ vasoactive intestinal polypeptide receptors isoforms and subtypes and its i soforms in a beta-cell Line and in isolated rat pancreatic islets. Although insulinoma cells express the messenger RNA encoding PAC1 (-R and -hop vari ants), VPAC1 and VPAC2, binding experiments indicate the preponderance of P AC1 over VPAC1-2 receptors. We have also shown that the main signaling path way of PACAP in beta-cells is mediated by adenylate cyclase, whereas the in ositol 1,4,5-trisphosphate pathway is almost inactive. Furthermore, we have demonstrated that PACAP exerts long-term effects on beta-cells, such as tr anscriptional regulation of the insulin gene and genes of the glucose-sensi ng system (GLUT1 and hexokinase 1).