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.