PT - JOURNAL ARTICLE AU - Jean-Philippe Fortin AU - Jonathan C. Schroeder AU - Yuantee Zhu AU - Martin Beinborn AU - Alan S. Kopin TI - Pharmacological Characterization of Human Incretin Receptor Missense Variants AID - 10.1124/jpet.109.160531 DP - 2009 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - jpet.109.160531 4099 - http://jpet.aspetjournals.org/content/early/2009/10/19/jpet.109.160531.short 4100 - http://jpet.aspetjournals.org/content/early/2009/10/19/jpet.109.160531.full AB - Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are gut-derived incretin hormones that regulate blood glucose levels. In addition to their widely accepted insulinotropic role, there is evidence that GLP-1 modulates feeding behavior and GIP regulates lipid metabolism thereby promoting postprandial fat deposition. In this study, we investigated whether naturally-occurring polymorphisms in the GLP-1 receptor (GLP-1R) and the GIP receptor (GIP-R) affect the pharmacological properties of these proteins. After transient expression of the receptors in HEK293 cells, basal as well as ligand-induced cAMP production were assessed using luciferase reporter gene assays. Our data reveal that the wild-type GIP-R displays a considerable degree of ligand-independent activity. In comparison, the GIP-R variants C46S, G198C, R316L and E354Q show a marked decrease in basal signaling that may, at least in part, be explained by reduced cell surface expression. When stimulated with GIP, the C46S and R316L mutants display significantly reduced potency (>1000 and 25- fold, respectively) compared to wild type. Complementary competition binding assays further demonstrate that the C46S variant fails to bind radio-iodinated GIP whereas all other GIP-R mutants maintain normal ligand affinity. In contrast to the GIP-R, the wild-type GLP-1R lacks constitutive activity. Furthermore, none of the ten GLP-1R missense mutations showed an alteration in pharmacological properties versus wild type. The extent to which abnormalities in GIP-R function may lead to physiological changes or affect drug sensitivity in selected populations (e.g. obese, diabetic individuals) remains to be further investigated.The American Society for Pharmacology and Experimental Therapeutics