Endocrinology, Vol 133, 1907-1910, Copyright © 1993 by Endocrine Society

ARTICLES

Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor

JS Dillon, Y Tanizawa, MB Wheeler, XH Leng, BB Ligon, DU Rabin, H Yoo-Warren, MA Permutt and AE Boyd 3d
Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, New England Medical Center, Tufts University School of Medicine, Boston, MA.

Truncated forms of glucagon-like peptide-1 are the most potent endogenous stimuli of insulin secretion and have powerful antidiabetogenic effects. To determine the structure and coupling mechanisms of the human GLP-1 receptor we have isolated two pancreatic islet cDNAs, encoding the 463 amino acid receptor and differing mainly in their 3' untranslated regions. The deduced amino acid sequence is 90% homologous with the rat GLP-1 receptor. Northern blot analysis shows expression of a single 2.7 kb transcript in pancreatic tissue. When expressed in COS-7 cells the recombinant receptor conferred specific, high affinity GLP-1(7-37) binding. GLP-1(7-37) increased intracellular cAMP in a concentration dependent manner and caused an increase in the free cytosolic calcium ([Ca2+]i) from an intracellular pool, characteristic of phospholipase C (PLC) activation. Thus, like the structurally related glucagon and parathyroid hormone receptors, the human GLP-1 receptor can activate multiple intracellular signaling pathways including adenylyl cyclase and PLC. Knowledge of the GLP-1 receptor structure will facilitate the development of receptor agonists and elucidation of the important role of GLP-1 in normal physiology and disease states.

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