The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

Research output: Contribution to journalArticle

Authors

  • Zijan Fang
  • Shiqian Chen
  • Philip Pickford
  • Johannes Broichhagen
  • Ivan R Corrêa
  • Sunil Kumar
  • Frederik Gorlitz
  • Christopher Dunsby
  • Paul French
  • Guy Rutter
  • Tricia M. Tan
  • Stephen R. Bloom
  • Ben Jones

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)345–360
Number of pages16
JournalACS Pharmacology & Translational Science
Volume3
Issue number2
Early online date17 Mar 2020
Publication statusPublished - 10 Apr 2020

Keywords

  • GLP-1R, exendin-4, biased signaling, membrane trafficking, endocytosis, recycling