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

Diabetes. 1993 Nov;42(11):1678-82. doi: 10.2337/diab.42.11.1678.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / analysis
  • Base Sequence
  • Cloning, Molecular
  • Cyclic AMP / analysis
  • Cyclic AMP / metabolism
  • DNA / analysis
  • DNA / genetics
  • Diabetes Mellitus, Type 2 / drug therapy
  • Exenatide
  • Gene Expression / genetics*
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Islets of Langerhans / chemistry
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / ultrastructure
  • Ligands
  • Molecular Sequence Data
  • Peptide Fragments / analysis
  • Peptide Fragments / pharmacology*
  • Peptides / analysis
  • Peptides / pharmacology*
  • Peptides / therapeutic use
  • Receptors, Cell Surface* / antagonists & inhibitors
  • Receptors, Cell Surface* / genetics
  • Receptors, Cell Surface* / physiology
  • Receptors, Glucagon*
  • Venoms*

Substances

  • Amino Acids
  • GLP1R protein, human
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Ligands
  • Peptide Fragments
  • Peptides
  • Receptors, Cell Surface
  • Receptors, Glucagon
  • Venoms
  • exendin (9-39)
  • DNA
  • Exenatide
  • Cyclic AMP

Associated data

  • GENBANK/D14315
  • GENBANK/D14316
  • GENBANK/D14317
  • GENBANK/D14318
  • GENBANK/L13313
  • GENBANK/L13314
  • GENBANK/L13315
  • GENBANK/L13316
  • GENBANK/U01104
  • GENBANK/X75014