Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells
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 comb...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2021
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/145775 |
| _version_ | 1824454004474642432 |
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| author | 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 |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) 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 |
| author_sort | Fang, Zijian |
| collection | NTU |
| description | 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. |
| first_indexed | 2025-02-19T03:15:25Z |
| format | Journal Article |
| id | ntu-10356/145775 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2025-02-19T03:15:25Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1457752023-03-05T16:49:34Z Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells 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 Lee Kong Chian School of Medicine (LKCMedicine) Science::Biological sciences Glucagon-like Peptide-1 Exendin-4 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. Published version 2021-01-07T08:39:26Z 2021-01-07T08:39:26Z 2020 Journal Article 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 1661-6596 https://hdl.handle.net/10356/145775 10.3390/ijms21218404 33182425 21 21 en International Journal of Molecular Sciences © 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/). application/pdf |
| spellingShingle | Science::Biological sciences Glucagon-like Peptide-1 Exendin-4 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 Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells |
| title | Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells |
| title_full | Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells |
| title_fullStr | Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells |
| title_full_unstemmed | Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells |
| title_short | Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells |
| title_sort | ligand specific factors influencing glp 1 receptor post endocytic trafficking and degradation in pancreatic beta cells |
| topic | Science::Biological sciences Glucagon-like Peptide-1 Exendin-4 |
| url | https://hdl.handle.net/10356/145775 |
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