CLONING AND FUNCTIONAL EXPRESSION OF THE HUMAN ISLET GLP-1 RECEPTOR -DEMONSTRATION THAT EXENDIN-4 IS AN AGONIST AND EXENDIN-(9-39) AN ANTAGONIST OF THE RECEPTOR

A complementary DNA for a glucagon-like peptide-1 receptor was isolate d from a human pancreatic islet cDNA library. The isolated clone encod ed a protein with 90% identity to the rat receptor. In stably transfec ted fibroblasts, the receptor bound [I-125]GLP-1 with high affinity (K (d) = 0.5 nM) and was coupled to adenylate cyclase as detected by a GL P-1-dependent increase in cAMP production (EC50 = 93 pM). Two peptides from the venom of the lizard Heloderma suspectum, exendin-4 and exend in-(9-39), displayed similar ligand binding affinities to the human GL P-1 receptor. Whereas exendin-4 acted as an agonist of the receptor, i nducing cAMP formation, exendin-(9-39) was an antagonist of the recept or, inhibiting GLP-1-induced cAMP production. Because GLP-1 has been p roposed as a potential agent for treatment of NIDDM, our present data will contribute to the characterization of the receptor binding site a nd the development of new agonists of this receptor.