Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/145775
Title: Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells
Authors: Fang, Zijian
Chen, Shiqian
Manchanda, Yusman
Bitsi, Stavroula
Pickford, Philip
David, Alessia
Shchepinova, Maria M.
Corrêa, Ivan R., Jr.
Hodson, David J.
Broichhagen, Johannes
Tate, Edward W.
Reimann, Frank
Salem, Victoria
Rutter, Guy A.
Tan, Tricia
Bloom, Stephen R.
Tomas, Alejandra
Jones, Ben
Keywords: Science::Biological sciences
Issue Date: 2020
Source: Fang, Z., Chen, S., Manchanda, Y., Bitsi, S., Pickford, P., David, A., . . . Jones, B. (2020). Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells. International Journal of Molecular Sciences, 21(21), 8404-. doi:10.3390/ijms21218404
Journal: International Journal of Molecular Sciences
Abstract: 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.
URI: https://hdl.handle.net/10356/145775
ISSN: 1661-6596
DOI: 10.3390/ijms21218404
Rights: © 2020 The Authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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