Real-time trafficking and signaling of the glucagon-like peptide-1 receptor |
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Authors: | Sarah Noerklit Roed,Pernille Wismann,Christina Rye Underwood,Nikolaj Kulahin,Helle Iversen,Karen Arevad Cappelen,Lauge Schä ffer,Janne Lehtonen,Jacob Hecksher-Soerensen,Anna Secher,Jesper Mosolff Mathiesen,Hans Brä uner-Osborne,Jennifer L. Whistler,Sanne Moeller Knudsen,Maria Waldhoer |
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Affiliation: | 1. Department of Incretin & Islet Biology, Novo Nordisk A/S, Maaloev, Denmark;2. Department of Diabetes Protein Engineering, Novo Nordisk A/S, Maaloev, Denmark;3. Department of Histology and Imaging, Novo Nordisk A/S, Maaloev, Denmark;4. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;5. Ernest Gallo Clinic and Research Center, Department of Neurology, University of California San Francisco, San Francisco, USA |
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Abstract: | 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. |
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Keywords: | Seven transmembrane-spanning receptors/G protein-coupled receptors Glucagon-like peptide-1 Trafficking cAMP signaling Fluorescent microscopy Real-time TR-FRET |
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