%0 Journal Article
%T The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists
%P 2020.02.24.961524
%* © 2020, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution-NonCommercial-NoDerivs 4.0 International), CC BY-NC-ND 4.0, as described at http://creativecommons.org/licenses/by-nc-nd/4.0/
%U https://www.biorxiv.org/content/10.1101/2020.02.24.961524v1
%X <h3>Abstract</h3> <p>Signal bias and membrane trafficking have recently emerged as important considerations in the therapeutic targeting of the glucagon-like peptide-1 receptor (GLP-1R) in type 2 diabetes and obesity. In the present study, we have evaluated a peptide series with varying sequence homology between native GLP-1 and exendin-4, the archetypal ligands on which approved GLP-1R agonists are based. We find notable differences in agonist-mediated signalling, endocytosis and recycling, dependent both on the introduction of a His → Phe switch at position 1 and the specific mid-peptide helical regions and C-termini of the two agonists. These observations were linked to insulin secretion in a beta cell model and provide insights into how ligand factors influence GLP-1R function at the cellular level.</p><h3>Graphical abstract</h3>
%G en
%J bioRxiv
%A Fang, Zijian
%A Chen, Shiqian
%A Pickford, Philip
%A Broichhagen, Johannes
%A Hodson, David J.
%A Corrêa, Ivan R.
%A Kumar, Sunil
%A Görlitz, Frederik
%A Dunsby, Christopher
%A French, Paul
%A Rutter, Guy A.
%A Tan, Tricia
%A Bloom, Stephen R.
%A Tomas, Alejandra
%A Jones, Ben
%D 2020-02-25
%K WP4