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Role of G Protein-Coupled Receptor Kinases in Glucose-Dependent Insulinotropic Polypeptide Receptor Signaling¹

Section of Gastroenterology, Boston Veterans Administration Medical Center, and Boston University School of Medicine, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Chi-Chuan Tseng, M.D., Ph.D., Section of Gastroenterology, Boston University School of Medicine, Boston, Massachusetts 02118.

The glucose-dependent insulinotropic polypeptide receptor (GIPR) is a member of class II G protein-coupled receptors. Recent studies have suggested that desensitization of the GIPR might contribute to impaired insulin secretion in type II diabetic patients, but the molecular mechanisms of GIPR signal termination are unknown. Using HEK L293 cells stably transfected with GIPR complementary DNA (L293-GIPR), the mechanisms of GIPR desensitization were investigated. GIP dose dependently increased intracellular cAMP levels in L293-GIPR cells, but this response was abolished (65%) by cotransfection with G protein-coupled receptor kinase 2 (GRK2), but not with GRK5 or GRK6. ß-Arrestin-1 transfection also induced a significantly decrease in GIP-stimulated cAMP production, and this effect was greater with cotransfection of both GRK2 and ß-arrestin-1 than with either alone. In ßTC3 cells, expression of GRK2 or ß-arrestin-1 attenuated GIP-induced insulin release and cAMP production, whereas glucose-stimulated insulin secretion was not affected. GRK2 and ß-arrestin-1 messenger RNAs were identified by Northern blot analysis to be expressed endogenously in ßTC3 and L293 cells. Overexpression of GRK2 enhanced agonist-induced GIPR phosphorylation, but receptor endocytosis was not affected by cotransfection with GRKs or ß-arrestin-1. These results suggest a potential role for GRK2/ß-arrestin-1 system in modulating GIP-mediated insulin secretion in pancreatic islet cells. Furthermore, GRK-mediated receptor phosphorylation is not required for endocytosis of the GIPR.

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