Through binding to high affinity receptors, secretin is the major hormonal stimulant of ductular bicarbonate secretion in the pancreas, contributes toward enzyme secretion from pancreatic acinar cells, and has been implicated as a pancreatic growth factor. In this work, we utilized hybridization screening of a human pancreatic cDNA library to clone a 1.8-kb cDNA encoding a 440 amino acid protein 81% identical to the rat pancreatic secretin receptor. COS-7 cells transfected with this cDNA bound secretin with a high affinity, and vasoactive intestinal peptide with a lower affinity, appropriate for a secretin receptor. Receptor-bearing COS-7 cells also exhibited an increase in cyclic AMP generation in response to secretin stimulation. Studies analyzing the role of this receptor in human pancreatic physiology and pathophysiology are currently underway in our laboratory.