10.1021/acsptsci.0c00022.s001 Zijian Fang Zijian Fang Shiqian Chen Shiqian Chen Philip Pickford Philip Pickford Johannes Broichhagen Johannes Broichhagen David J. Hodson David J. Hodson Ivan R. Corrêa Ivan R. Corrêa Sunil Kumar Sunil Kumar Frederik Görlitz Frederik Görlitz Chris Dunsby Chris Dunsby Paul M. W. French Paul M. W. French Guy A. Rutter Guy A. Rutter Tricia Tan Tricia Tan Stephen R. Bloom Stephen R. Bloom Alejandra Tomas Alejandra Tomas Ben Jones Ben Jones The Influence of Peptide Context on Signaling and Trafficking of Glucagon-like Peptide‑1 Receptor Biased Agonists American Chemical Society 2020 Peptide Context insulin secretion midpeptide helical regions membrane trafficking ligand factors influence GLP -1R function beta cell model GLP -1R β- arrestins agonist-mediated cyclic AMP position 1 archetypal ligands sequence homology glucagon-like peptide type 2 diabetes GLP -1R agonists peptide series 2020-03-26 20:45:26 Journal contribution 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 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.