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 isolated from a human pancreatics islet cDNA library. The isolated clone encoded a protein with 90% identity to the rat receptor. In stably transfected fibroblasts, the receptor bound [¹²⁵I]GLP-1 with high affinity (K_d = 0.5 nM) and was coupled to adenylate cyclase as detected by a GLP-1-dependent increase in cAMP production (EC₅₀ = 93 pM). Two peptides from the venom of the lizard Heloderma suspectum, exendin-4 and exendin-(9–39), displayed similar ligand binding affinities to the human GLP-1 receptor. Whereas exendin-4 acted as an agonist of the receptor, inducing cAMP formation, exendin-(9–39) was an antagonist of the receptor, inhibiting GLP-1–induced cAMP production. Because GLP-1 has been proposed as a potential agent for treatment of NIDDM, our present data will contribute to the characterization of the receptor binding site and the development of new agonists of this receptor.