title: The amino terminal domain of the glucagon-like peptide-1 receptor is a critical determinant of subtype specificity.
abstract: Glucagon-like peptide-1 (GLP-1) and glucagon are peptide hormones involved in glucose homeostasis. The ligands are closely related (48% identical) and bind with different affinities to distinct, although highly homologous (47% identical), G protein coupled receptors on the surface of cells. By these criteria, glucagon and GLP-1 receptors can be considered receptor subtypes. A series of chimeric receptors in which 4-6 amino acids in the N-terminal extracellular domain of the human GLP-1 receptor were replaced with the analogous region of the human glucagon receptor were constructed and expressed in COS-7 cells. One of these chimeric receptors, C29-32 displays a 7 to 10-fold decrease in affinity for GLP-1 and the GLP-1 antagonist exendin 9-39 amide and a concomitant 7 to 9-fold increase in its affinity for glucagon. This change in affinity results in a 50-fold decrease in the selectivity of this receptor for GLP-1 over glucagon. Thus, the substitution of as few as four residues of the GLP-1 receptor profoundly affects its selectivity for the homologous peptide agonists GLP-1 and glucagon. These results suggest the extracellular N terminal domain of the GLP-1 receptor harbours molecular determinants for both agonist binding affinity and selectivity.
authors.affiliation: Department of Molecular Pharmacology and Biochemistry, Merck Research Laboratories, Rahway NJ 07065, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Graziano
authors.forename: P J
authors.initials: PJ
authors.lastname: Hey
authors.forename: C D
authors.initials: CD
authors.lastname: Strader
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000096:biosynthesis; D000077270:Exenatide; D005934:Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D018027:Receptors, Glucagon / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D014688:Venoms
chemical_list: C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D014688:Venoms; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000077270:Exenatide; D000242:Cyclic AMP