Real-time trafficking and signaling of the glucagon-like peptide-1 receptor
Open accessAbstract
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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Each GLP-1, GIP, and glucagon receptor undergoes agonist-induced endocytosis to varying degrees, fine-tuning spatial and temporal modulation of intracellular signaling and hormonal response.
“Each receptor undergoes agonist-induced endocytosis to varying degrees, thus fine-tuning spatial and temporal modulation of intracellular signaling and hormonal response [28].”
From New Developments in Pharmacological Treatment of Obesity and Type 2 Diabetes—Beyond and within GLP-1 Receptor Agonists (2024) · cites this paper as [28]
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- Authors
- 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. L., Knudsen, S. M., & Waldhoer, M.
- Affiliations
- Novo Nordisk (Denmark) (DK)
- University of Copenhagen (DK)
- University of California, San Francisco (US)
- ORCID
- Venue
- Molecular and Cellular Endocrinology
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 382
- Issue
- 2
- Pages
- 938-949
- ISSN
- 0303-7207 (ISSN-L)
- OpenAlex
- W1987856394
- Cited by
- 153
- References
- 25
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 7 · 2023: 8 · 2022: 14 · 2021: 16 · 2020: 17 · 2019: 15 · 2018: 11 · 2017: 9 · 2016: 13 · 2015: 13 · 2014: 9
- FWCI
- 5.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular and Cellular Endocrinology (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd
- Lundbeckfonden
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- GLP-1 receptor, G protein-coupled receptors, receptor internalization, receptor recycling, receptor trafficking, exendin-4, liraglutide, GLP-1 analogues, cAMP signaling, pancreatic islets, type 2 diabetes
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Liraglutide, Exenatide, Cyclic AMP, Animals, Humans, Islets of Langerhans, Mice, Inbred C57BL, Peptides, Venoms, Signal Transduction, Receptors, Glucagon, Protein Transport, Mice, Glucagon-Like Peptide 1, Incretins, Protein Stability, HEK293 Cells, Time-Lapse Imaging, Proteolysis
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