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Article

Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells

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Section of Endocrinology and Investigative Medicine, Imperial College London, London W12 0NN, UK
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Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute and Department of Haematology, University of Cambridge, Cambridge CB2 0AW, UK
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Section of Cell Biology and Functional Genomics, Imperial College London, London W12 0NN, UK
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Centre for Bioinformatics and System Biology, Department of Life Sciences, Imperial College London, London SW7 2BX, UK
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Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, 80 Wood Lane, London W12 0BZ, UK
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New England Biolabs, Ipswich, MA 01938, USA
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Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham B15 2TT, UK
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
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Department of Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, 13125 Berlin, Germany
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Department of Chemical Biology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany
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Institute of Metabolic Science & MRC Metabolic Diseases Unit, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK
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Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 639798, Singapore
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(21), 8404; https://doi.org/10.3390/ijms21218404
Received: 7 October 2020 / Revised: 1 November 2020 / Accepted: 2 November 2020 / Published: 9 November 2020
(This article belongs to the Special Issue Journey inside the Beta Cells in Type 2 Diabetes)
The glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of blood glucose homeostasis. Ligand-specific differences in membrane trafficking of the GLP-1R influence its signalling properties and therapeutic potential in type 2 diabetes. Here, we have evaluated how different factors combine to control the post-endocytic trafficking of GLP-1R to recycling versus degradative pathways. Experiments were performed in primary islet cells, INS-1 832/3 clonal beta cells and HEK293 cells, using biorthogonal labelling of GLP-1R to determine its localisation and degradation after treatment with GLP-1, exendin-4 and several further GLP-1R agonist peptides. We also characterised the effect of a rare GLP1R coding variant, T149M, and the role of endosomal peptidase endothelin-converting enzyme-1 (ECE-1), in GLP1R trafficking. Our data reveal how treatment with GLP-1 versus exendin-4 is associated with preferential GLP-1R targeting towards a recycling pathway. GLP-1, but not exendin-4, is a substrate for ECE-1, and the resultant propensity to intra-endosomal degradation, in conjunction with differences in binding affinity, contributes to alterations in GLP-1R trafficking behaviours and degradation. The T149M GLP-1R variant shows reduced signalling and internalisation responses, which is likely to be due to disruption of the cytoplasmic region that couples to intracellular effectors. These observations provide insights into how ligand- and genotype-specific factors can influence GLP-1R trafficking. View Full-Text
Keywords: glucagon-like peptide-1; exendin-4; trafficking; biased agonism; degradation; endothelin converting enzyme-1 glucagon-like peptide-1; exendin-4; trafficking; biased agonism; degradation; endothelin converting enzyme-1
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MDPI and ACS Style

Fang, Z.; Chen, S.; Manchanda, Y.; Bitsi, S.; Pickford, P.; David, A.; Shchepinova, M.M.; Corrêa Jr, I.R.; Hodson, D.J.; Broichhagen, J.; Tate, E.W.; Reimann, F.; Salem, V.; Rutter, G.A.; Tan, T.; Bloom, S.R.; Tomas, A.; Jones, B. Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells. Int. J. Mol. Sci. 2020, 21, 8404. https://doi.org/10.3390/ijms21218404

AMA Style

Fang Z, Chen S, Manchanda Y, Bitsi S, Pickford P, David A, Shchepinova MM, Corrêa Jr IR, Hodson DJ, Broichhagen J, Tate EW, Reimann F, Salem V, Rutter GA, Tan T, Bloom SR, Tomas A, Jones B. Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells. International Journal of Molecular Sciences. 2020; 21(21):8404. https://doi.org/10.3390/ijms21218404

Chicago/Turabian Style

Fang, Zijian, Shiqian Chen, Yusman Manchanda, Stavroula Bitsi, Philip Pickford, Alessia David, Maria M. Shchepinova, Ivan R. Corrêa Jr, David J. Hodson, Johannes Broichhagen, Edward W. Tate, Frank Reimann, Victoria Salem, Guy A. Rutter, Tricia Tan, Stephen R. Bloom, Alejandra Tomas, and Ben Jones. 2020. "Ligand-Specific Factors Influencing GLP-1 Receptor Post-Endocytic Trafficking and Degradation in Pancreatic Beta Cells" International Journal of Molecular Sciences 21, no. 21: 8404. https://doi.org/10.3390/ijms21218404

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