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. 2014 Feb 15;382(2):938-49.
doi: 10.1016/j.mce.2013.11.010. Epub 2013 Nov 22.

Real-time trafficking and signaling of the glucagon-like peptide-1 receptor

Sarah Noerklit Roed  1 , Pernille Wismann  2 , Christina Rye Underwood  2 , Nikolaj Kulahin  2 , Helle Iversen  2 , Karen Arevad Cappelen  2 , Lauge Schäffer  3 , Janne Lehtonen  4 , Jacob Hecksher-Soerensen  4 , Anna Secher  4 , Jesper Mosolff Mathiesen  5 , Hans Bräuner-Osborne  5 , Jennifer L Whistler  6 , Sanne Moeller Knudsen  2 , Maria Waldhoer  2
Affiliations
Free article

Real-time trafficking and signaling of the glucagon-like peptide-1 receptor

Sarah Noerklit Roed et al. Mol Cell Endocrinol. .
Free article

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.

Keywords: Fluorescent microscopy; Glucagon-like peptide-1; Real-time TR-FRET; Seven transmembrane-spanning receptors/G protein-coupled receptors; Trafficking; cAMP signaling.

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