Imperial College London
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Dr Alejandra Tomas

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 3364a.tomas-catala Website CV

 
 
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Location

 

329ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Jones:2020:10.3390/ijms21218404,
author = {Jones, B and Fang, Z and Chen, S and Manchanda, Y and Bitsi, S and Pickford, P and David, A and Shchepinova, MM and Corrêa, Jr IR and Hodson, DJ and Broichhagen, J and Tate, EW and Reimann, F and Salem, V and Rutter, GA and Tan, T and Bloom, SR and Tomas, A},
doi = {10.3390/ijms21218404},
journal = {International Journal of Molecular Sciences},
pages = {1--24},
title = {Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells},
url = {http://dx.doi.org/10.3390/ijms21218404},
volume = {212},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
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.
AU  - Jones,B
AU  - Fang,Z
AU  - Chen,S
AU  - Manchanda,Y
AU  - Bitsi,S
AU  - Pickford,P
AU  - David,A
AU  - Shchepinova,MM
AU  - Corrêa,Jr IR
AU  - Hodson,DJ
AU  - Broichhagen,J
AU  - Tate,EW
AU  - Reimann,F
AU  - Salem,V
AU  - Rutter,GA
AU  - Tan,T
AU  - Bloom,SR
AU  - Tomas,A
DO  - 10.3390/ijms21218404
EP  - 24
PY  - 2020///
SN  - 1422-0067
SP  - 1
TI  - Ligand-specific factors influencing GLP-1 receptor post-endocytic trafficking and degradation in pancreatic beta cells
T2  - International Journal of Molecular Sciences
UR  - http://dx.doi.org/10.3390/ijms21218404
UR  - https://www.mdpi.com/1422-0067/21/21/8404
UR  - http://hdl.handle.net/10044/1/84936
VL  - 212
ER  -
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