title: Selectivity of peptide ligands for the human incretin receptors expressed in HEK-293 cells.
abstract: The increase in insulin response to oral glucose compared with glucose given by intravenous injection is termed the incretin effect and is mediated by two peptide hormones secreted from the gut in response to nutrient intake: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP exert their insulinotropic effects through their respective receptors expressed on pancreatic β-cells. Both the GLP-1 receptor and the GIP receptor are members of the secretin family of G protein-coupled receptors and couple positively with adenylate cyclase, resulting in an increase in intracellular cAMP. In the present study, we investigated the activity of six previously reported peptide ligands at both the GLP-1 and GIP receptors expressed on HEK-293 cells using a highly sensitive reporter gene assay. GLP-1 and GIP demonstrated almost 100,000-fold selectivity for their respective receptors. Exendin 4 (Ex-4), a long-acting GLP-1 receptor agonist, displayed considerable activity at the GIP receptor. Exendin 9-39 (Ex 9-39) was able to block activity at both the GLP-1 and GIP receptors, and Pro3GIP, a previously-reported GIP receptor antagonist, was shown to act as a partial agonist at the GIP receptor. These data highlight the need for more selective antagonists to study these therapeutically important receptors.
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, PO Box 24923, 13110 Safat, Kuwait. Electronic address: Suleiman@hsc.edu.kw.
authors.forename: S
authors.initials: S
authors.lastname: Al-Sabah
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, PO Box 24923, 13110 Safat, Kuwait.
authors.forename: M
authors.initials: M
authors.lastname: Al-Fulaij
authors.affiliation: Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, PO Box 24923, 13110 Safat, Kuwait.
authors.forename: H A
authors.initials: HA
authors.lastname: Ahmed
mesh_terms: D000595:Amino Acid Sequence; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D000067757:Glucagon-Like Peptide-1 Receptor; D057809:HEK293 Cells; D006801:Humans; D054795:Incretins / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011964:Receptors, Gastrointestinal Hormone / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D054795:Incretins; D008024:Ligands; D010446:Peptide Fragments; D011964:Receptors, Gastrointestinal Hormone; D018027:Receptors, Glucagon; C041086:gastric inhibitory polypeptide receptor
keywords: G protein-coupled receptor; GIP; GLP-1; Pro3GIP