OBJECTIVE The presence of cholecystokinin (CCK)-B/gastrin receptors in the pancreas of higher mammals including humans has been shown, but their physiological function in the normal pancreas is unknown. The aim of this study was to investigate whether they couple to the secretory machinery of normal acinar cells. METHODS A transgenic mouse strain expressing the human CCK-B/gastrin receptor in the exocrine pancreas was created. The transgenic construction used the promoter region of the elastase I gene and the human CCK-B/gastrin receptor gene. Analysis of ElasCCKB mice included polymerase chain reaction and receptor autoradiography. Molecular and binding features of the CCK-B/gastrin receptor were determined by Western blot and radioligand binding studies. Amylase secretion and inositol phosphate production assays were used in functional characterization. RESULTS The CCK-B/gastrin receptor was expressed in the exocrine pancreas and had typical molecular and binding features. CCK and sulfated gastrin stimulated enzyme secretion with identical potencies and efficacies. They activated phospholipase C, but CCK was 60-fold less potent than sulfated gastrin. CONCLUSIONS The data show that the CCK-B/gastrin receptor mediates exocytosis in acinar cells and can differentially couple to phospholipase C depending on the agonist. The ElasCCKB mice provide a useful model to study phospholipase C-dependent and -independent intracellular transduction pathways leading to pancreatic exocrine secretion.