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Real-time trafficking and signaling of the glucagon-like peptide-1 receptor
- Roed, Sarah Noerklit, Wismann, Pernille, Underwood, Christina Rye, Kulahin, Nikolaj, Iversen, Helle, Cappelen, Karen Arevad, Schäffer, Lauge, Lehtonen, Janne, Hecksher-Soerensen, Jacob, Secher, Anna, Mathiesen, Jesper Mosolff, Bräuner-Osborne, Hans, Whistler, Jennifer L., Knudsen, Sanne Moeller, Waldhoer, Maria
- Molecular and Cellular Endocrinology 2014 v.382 pp. 938-949
- G-protein coupled receptors, blood glucose, cyclic AMP, drugs, glucagon-like peptide 1, humans, islets of Langerhans, mice, microscopy, secretin
- The glucagon-like peptide-1 incretin receptor (GLP-1R) of family B G protein-coupled receptors (GPCRs) is a major drug target in type-2-diabetes due to its regulatory effect on post-prandial blood-glucose levels. The mechanism(s) controlling GLP-1R mediated signaling are far from fully understood. A fundamental mechanism controlling the signaling capacity of GPCRs is the post-endocytic trafficking of receptors between recycling and degradative fates. Here, we combined microscopy with novel real-time assays to monitor both receptor trafficking and signaling in living cells. We find that the human GLP-1R internalizes rapidly and with similar kinetics in response to equipotent concentrations of GLP-1 and the stable GLP-1 analogues exendin-4 and liraglutide. Receptor internalization was confirmed in mouse pancreatic islets. GLP-1R is shown to be a recycling receptor with faster recycling rates mediated by GLP-1 as compared to exendin-4 and liraglutide. Furthermore, a prolonged cycling of ligand-activated GLP-1Rs was observed and is suggested to be correlated with a prolonged cAMP signal.