Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor.
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.
Dillon
J S
JS
Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, New England Medical Center, Tufts University School of Medicine, Boston, MA.
Tanizawa
Y
Y
Wheeler
M B
MB
Leng
X H
XH
Ligon
B B
BB
Rabin
D U
DU
Yoo-Warren
H
H
Permutt
M A
MA
Boyd
A E
AE
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D018027:Receptors, Glucagon; D015290:Second Messenger Systems; D014018:Tissue Distribution
D018076:DNA, Complementary; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D015335:Molecular Probes; D011956:Receptors, Cell Surface; D018027:Receptors, Glucagon; D000242:Cyclic AMP; D002118:Calcium