%0 Journal Article %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, Chris %A French, Paul M. W. %A Rutter, Guy A. %A Tan, Tricia %A Bloom, Stephen R. %A Tomas, Alejandra %A Jones, Ben %D 2020 %T The Influence of Peptide Context on Signaling and Trafficking of Glucagon-like Peptide‑1 Receptor Biased Agonists %U https://acs.figshare.com/articles/journal_contribution/The_Influence_of_Peptide_Context_on_Signaling_and_Trafficking_of_Glucagon-like_Peptide_1_Receptor_Biased_Agonists/12037491 %R 10.1021/acsptsci.0c00022.s001 %2 https://acs.figshare.com/ndownloader/files/22121274 %K Peptide Context %K insulin secretion %K midpeptide helical regions %K membrane trafficking %K ligand factors influence GLP -1R function %K beta cell model %K GLP -1R %K β- arrestins %K agonist-mediated cyclic AMP %K position 1 %K archetypal ligands %K sequence homology %K glucagon-like peptide %K type 2 diabetes %K GLP -1R agonists %K peptide series %X 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 cyclic AMP signaling, recruitment of β-arrestins, endocytosis, and recycling, dependent both on the introduction of a His → Phe switch at position 1 and the specific midpeptide 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. %I ACS Publications