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 pancreatic 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 (Kd = 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.
Thorens
B
B
Department of Pharmacology and Toxicology, University of Lausanne, Switzerland.
Porret
A
A
Bühler
L
L
Deng
S P
SP
Morel
P
P
Widmann
C
C
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis; D001483:Base Sequence; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism; D004247:DNA / Q000032:analysis / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D000077270:Exenatide; D015870:Gene Expression / Q000235:genetics*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007515:Islets of Langerhans / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D008024:Ligands; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000032:analysis / Q000494:pharmacology*; D010455:Peptides / Q000032:analysis / Q000494:pharmacology* / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D018027:Receptors, Glucagon; D014688:Venoms
D000596:Amino Acids; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; D011956:Receptors, Cell Surface; D018027:Receptors, Glucagon; D014688:Venoms; C083773:exendin (9-39); D004247:DNA; D000077270:Exenatide; D000242:Cyclic AMP