The Influence of Peptide Context on Signaling and Trafficking of Glucagon-like Peptide‑1 Receptor Biased Agonists Zijian Fang Shiqian Chen Philip Pickford Johannes Broichhagen David J. Hodson Ivan R. Corrêa Sunil Kumar Frederik Görlitz Chris Dunsby Paul M. W. French Guy A. Rutter Tricia Tan Stephen R. Bloom Alejandra Tomas Ben Jones 10.1021/acsptsci.0c00022.s001 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. 2020-03-26 20:45:26 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