Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells

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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; Corrêa, Ivan R; Hodson, David; Broichhagen, Johannes; Tate, Edward ; Reimann, Frank; Salem, Victoria; Rutter, Guy; Tan, Tricia M.; Bloom, Stephen R.; Tomas, Alejandra; Jones, Ben.

In: International Journal of Molecular Sciences, Vol. 21, No. 21, 8404, 09.11.2020.

Research output: Contribution to journalArticlepeer-review

Harvard

Fang, Z, Chen, S, Manchanda, Y, Bitsi, S, Pickford, P, David, A, Shchepinova, M, Corrêa, IR, Hodson, D, Broichhagen, J, Tate, E, Reimann, F, Salem, V, Rutter, G, Tan, TM, Bloom, SR, Tomas, 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, vol. 21, no. 21, 8404. https://doi.org/10.3390/ijms21218404

APA

Fang, Z., Chen, S., Manchanda, Y., Bitsi, S., Pickford, P., David, A., Shchepinova, M., Corrêa, I. R., Hodson, D., Broichhagen, J., Tate, E., Reimann, F., Salem, V., Rutter, G., Tan, T. M., Bloom, S. R., Tomas, 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]. https://doi.org/10.3390/ijms21218404

Vancouver

Author

Fang, Zijian ; Chen, Shiqian ; Manchanda, Yusman ; Bitsi, Stavroula ; Pickford, Philip ; David, Alessia ; Shchepinova, Maria ; Corrêa, Ivan R ; Hodson, David ; Broichhagen, Johannes ; Tate, Edward ; Reimann, Frank ; Salem, Victoria ; Rutter, Guy ; Tan, Tricia M. ; Bloom, Stephen R. ; Tomas, Alejandra ; Jones, Ben. / Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells. In: International Journal of Molecular Sciences. 2020 ; Vol. 21, No. 21.

Bibtex

@article{e2a63a797732427f82d07cb1b83fae34,
title = "Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells",
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.",
keywords = "glucagon-like peptide-1, exendin-4, trafficking, biased agonism, degradation, endothelin converting enzyme-1",
author = "Zijian Fang and Shiqian Chen and Yusman Manchanda and Stavroula Bitsi and Philip Pickford and Alessia David and Maria Shchepinova and Corr{\^e}a, {Ivan R} and David Hodson and Johannes Broichhagen and Edward Tate and Frank Reimann and Victoria Salem and Guy Rutter and Tan, {Tricia M.} and Bloom, {Stephen R.} and Alejandra Tomas and Ben Jones",
year = "2020",
month = nov,
day = "9",
doi = "10.3390/ijms21218404",
language = "English",
volume = "21",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "MDPI",
number = "21",

}

RIS

TY - JOUR

T1 - Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells

AU - Fang, Zijian

AU - Chen, Shiqian

AU - Manchanda, Yusman

AU - Bitsi, Stavroula

AU - Pickford, Philip

AU - David, Alessia

AU - Shchepinova, Maria

AU - Corrêa, Ivan R

AU - Hodson, David

AU - Broichhagen, Johannes

AU - Tate, Edward

AU - Reimann, Frank

AU - Salem, Victoria

AU - Rutter, Guy

AU - Tan, Tricia M.

AU - Bloom, Stephen R.

AU - Tomas, Alejandra

AU - Jones, Ben

PY - 2020/11/9

Y1 - 2020/11/9

N2 - 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.

AB - 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.

KW - glucagon-like peptide-1

KW - exendin-4

KW - trafficking

KW - biased agonism

KW - degradation

KW - endothelin converting enzyme-1

U2 - 10.3390/ijms21218404

DO - 10.3390/ijms21218404

M3 - Article

VL - 21

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 21

M1 - 8404

ER -