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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cyclic AMP / metabolism
  • Exenatide
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Like Peptide-1 Receptor
  • HEK293 Cells
  • Humans
  • Incretins / metabolism
  • Incretins / pharmacology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / ultrastructure
  • Liraglutide
  • Mice
  • Mice, Inbred C57BL
  • Peptides / metabolism
  • Peptides / pharmacology
  • Protein Stability
  • Protein Transport
  • Proteolysis
  • Receptors, Glucagon / metabolism*
  • Signal Transduction / drug effects*
  • Time-Lapse Imaging
  • Venoms / metabolism
  • Venoms / pharmacology


  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Incretins
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Exenatide
  • Cyclic AMP