CLONING, FUNCTIONAL EXPRESSION, AND CHROMOSOMAL LOCALIZATION OF THE HUMAN PANCREATIC-ISLET GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE RECEPTOR

Glucose-dependent insulinotropic polypeptide (GIP) is a hormone secret ed by the endocrine K-cells from the duodenum that stimulates glucose- induced insulin secretion, Here, we present the molecular characteriza tion of the human pancreatic islet GIP receptor, cDNA clones for the G IP receptor were isolated from a human pancreatic islet cDNA library, They encoded two different forms of the receptor, which differed by a 27-amino acid insertion in the COOH-terminal cytoplasmic tail, The rec eptor protein sequence was 81% identical to that of the rat GIP recept or, When expressed in Chinese hamster lung fibroblasts, both forms of the receptor displayed high-affinity binding for GIP (180 and 600 pmol /l), GIP binding was displaced by <20% by 1 mu mol/l glucagon, glucago n-like peptide (GLP-I)(7-36) amide, vasoactive intestinal peptide, and secretin, However exendin-4 and exendin-(9-39) at 1 mu mol/l displace d binding by similar to 70 and similar to 100% at 10 mu mol/l. GIP bin ding to both forms of the receptor induced a dose-dependent increase i n intracellular cAMP levels (EC(50) values of 0.6-0.8 nmol/l) but no e levation of cytoplasmic calcium concentrations, Interestingly, both ex endin-4 and exendin-(939) were antagonists of the receptor, inhibiting GIP-induced cAMP formation by up to 60% when present at a concentrati on of 10 mu mol/l. Finally, the physical and genetic chromosomal local ization of the receptor gene was determined to be on 19q13.3, close to the ApoC2 gene, These data will help study the physiology and pathoph ysiology of the human GIP receptor.