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

Sarah Noerklit Roed, Pernille Wismann, Christina Rye Underwood, Nikolaj Kulahin, Helle Iversen, Karen Arevad Cappelen, Lauge Schäffer, Janne Lehtonen, Jacob Hecksher-Soerensen, Anna Secher, Jesper Mosolff Mathiesen, Hans Bräuner-Osborne, Jennifer Whistler, Sanne Moeller Knudsen, Maria Waldhoer

Research output: Contribution to journalArticle

61 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)938-949
Number of pages12
JournalMolecular and Cellular Endocrinology
Volume382
Issue number2
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

    Fingerprint

Keywords

  • CAMP signaling
  • Fluorescent microscopy
  • Glucagon-like peptide-1
  • Real-time TR-FRET
  • Seven transmembrane-spanning receptors/G protein-coupled receptors
  • Trafficking

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

Roed, S. N., Wismann, P., Underwood, C. R., Kulahin, N., Iversen, H., Cappelen, K. A., Schäffer, L., Lehtonen, J., Hecksher-Soerensen, J., Secher, A., Mathiesen, J. M., Bräuner-Osborne, H., Whistler, J., Knudsen, S. M., & Waldhoer, M. (2014). Real-time trafficking and signaling of the glucagon-like peptide-1 receptor. Molecular and Cellular Endocrinology, 382(2), 938-949. https://doi.org/10.1016/j.mce.2013.11.010