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 L Whistler; Sanne Moeller Knudsen; Maria Waldhoer

doi:10.1016/j.mce.2013.11.010

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 L Whistler, Sanne Moeller Knudsen, Maria Waldhoer

87 Citations (Scopus)

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 language	English
Journal	Molecular and Cellular Endocrinology
Volume	382
Issue number	2
Pages (from-to)	938-949
Number of pages	12
ISSN	0303-7207
DOIs	https://doi.org/10.1016/j.mce.2013.11.010
Publication status	Published - Feb 2014

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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. (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

Roed, SN, Wismann, P, Underwood, CR, Kulahin, N, Iversen, H, Cappelen, KA, Schäffer, L, Lehtonen, J, Hecksher-Soerensen, J, Secher, A, Mathiesen, JM , Bräuner-Osborne, H, Whistler, JL, Knudsen, SM & Waldhoer, M 2014, 'Real-time trafficking and signaling of the glucagon-like peptide-1 receptor', Molecular and Cellular Endocrinology, vol. 382, no. 2, pp. 938-949. https://doi.org/10.1016/j.mce.2013.11.010

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title = "Real-time trafficking and signaling of the glucagon-like peptide-1 receptor",

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.",

author = "Roed, {Sarah Noerklit} and Pernille Wismann and Underwood, {Christina Rye} and Nikolaj Kulahin and Helle Iversen and Cappelen, {Karen Arevad} and Lauge Sch{\"a}ffer and Janne Lehtonen and Jacob Hecksher-Soerensen and Anna Secher and Mathiesen, {Jesper Mosolff} and Hans Br{\"a}uner-Osborne and Whistler, {Jennifer L} and Knudsen, {Sanne Moeller} and Maria Waldhoer",

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AU - Roed, Sarah Noerklit

AU - Wismann, Pernille

AU - Underwood, Christina Rye

AU - Kulahin, Nikolaj

AU - Iversen, Helle

AU - Cappelen, Karen Arevad

AU - Schäffer, Lauge

AU - Lehtonen, Janne

AU - Hecksher-Soerensen, Jacob

AU - Secher, Anna

AU - Mathiesen, Jesper Mosolff

AU - Bräuner-Osborne, Hans

AU - Whistler, Jennifer L

AU - Knudsen, Sanne Moeller

AU - Waldhoer, Maria

PY - 2014/2

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N2 - 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.

AB - 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.

U2 - 10.1016/j.mce.2013.11.010

DO - 10.1016/j.mce.2013.11.010

M3 - Journal article

C2 - 24275181

SN - 0303-7207

VL - 382

SP - 938

EP - 949

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

IS - 2

ER -

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

Abstract

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