Signal transduction of the GLP‐1‐receptor cloned from a human insulinoma

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Abstract
GLP‐1 (glucagon‐like peptide 1 (7–36) amide) plays an important role in the regulation of insulin secretion and proinsulin gene expression of pancreatic β‐cells. Patients with insulinoma tumors show uncontrolled insulin hypersecretion. This study demonstrates the molecular cloning of a cDNA for the GLP‐1 receptor from a human insulinoma employing a λ‐gt 11 cDNA library. The cloned cDNA encoded a seven transmembrane domain protein of 463 amino acids which showed high homology to the GLP‐1 receptor in normal human pancreas. Four amino acid exchanges were found in comparison to a receptor sequence obtained from regular pancreatic islets. When transfected transiently into COS‐7 or stably into fibroblast CHL cells a high affinity receptor was expressed which coupled to the adenylate cyclase with normal basal cAMP and increasing intracellular cAMP levels under GLP‐1 stimulation. The receptor accepted GLP‐1 and the non‐mammalian agonist exendin‐4 as high affinity ligands. In transfected COS‐7 cells, GLP‐1 did not influence intracellular calcium, whereas in the stably transfected fibroblasts GLP‐1 transiently increased intracellular calcium to a small extent. The understanding of GLP‐1 receptor regulation and signal transduction will aid in the discovery of compounds that act as agonists of the GLP‐1 receptor for potential use in the treatment of diabetes and will facilitate the understanding of its expression under normal and pathophysiological conditions.