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

Overview

Journal ACS Pharmacol Transl Sci

Publisher American Chemical Society

Specialty Biochemistry

Date 2020 Apr 17

PMID 32296773

Citations 19

Authors

Zijian Fang

Shiqian Chen

Philip Pickford

Johannes Broichhagen

David J Hodson

Ivan R Correa Jr

Sunil Kumar

Frederik Gorlitz

Chris Dunsby

Paul M W French

Guy A Rutter

Tricia Tan

Stephen R Bloom

Alejandra Tomas

Ben Jones

Affiliations

Soon will be listed here.

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.

Citing Articles

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