The Influence of Peptide Context on Signaling and Trafficking of Glucagon-like Peptide-1 Receptor Biased Agonists.

Abstract

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.

• Authors: Zijian Fang, Shiqian Chen, Philip Pickford, Johannes Broichhagen, David J Hodson, Ivan R Corrêa Jr, Sunil Kumar, Frederik Görlitz, Chris Dunsby, Paul M W French, Guy A Rutter, Tricia Tan, Stephen R Bloom, Alejandra Tomas, Ben Jones
• Journal: ACS pharmacology & translational science (ACS Pharmacol Transl Sci) Vol. 3 Issue 2 Pg. 345-360 (Apr 10 2020) ISSN: 2575-9108 [Electronic] United States
• PMID: 32296773 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 American Chemical Society.