BibTex format

author = {Pickford, P and Lucey, M and Fang, Z and Bitsi, S and Bernardino, de la Serna J and Broichhagen, J and Hodson, DJ and Minnion, J and Rutter, GA and Bloom, SR and Tomas, A and Jones, B},
doi = {10.1111/bph.15134},
journal = {British Journal of Pharmacology},
pages = {3905--3923},
title = {Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide.},
url = {},
volume = {177},
year = {2020}

RIS format (EndNote, RefMan)

AB - BACKGROUND AND PURPOSE: Amino acid substitutions at the N-termini of glucagon-like peptide-1 receptor agonist (GLP-1RA) peptides result in distinct patterns of intracellular signalling, sub-cellular trafficking and efficacy in vivo. Here we aimed to determine whether sequence differences at the ligand C-termini of clinically approved GLP-1RAs exendin-4 and lixisenatide lead to similar phenomena. EXPERIMENTAL APPROACH: Exendin-4, lixisenatide, and N-terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types. Fluorescent ligands and new time-resolved FRET approaches were developed to study agonist behaviours at the cellular and sub-cellular level. Anti-hyperglycaemic and anorectic effects of each parent ligand, and their biased derivatives, were assessed in mice. KEY RESULTS: Lixisenatide and exendin-4 showed equal binding affinity, but lixisenatide was 5-fold less potent for cAMP signalling. Both peptides induced extensive GLP-1R clustering in the plasma membrane and were rapidly endocytosed, but the GLP-1R recycled more slowly to the cell surface after lixisenatide treatment. These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti-hyperglycaemic and anorectic effects in mice with lixisenatide. N-terminal substitution of His1 by Phe1 to both ligands had favourable effects on their pharmacology, resulting in improved insulin release and lowering of blood glucose. CONCLUSION AND IMPLICATIONS: Changes to the C-terminus of exendin-4 affect signalling potency and GLP-1R trafficking via mechanisms unrelated to GLP-1R occupancy. These differences were associated with changes in their ability to control blood glucose and therefore may be therapeutically relevant.
AU - Pickford,P
AU - Lucey,M
AU - Fang,Z
AU - Bitsi,S
AU - Bernardino,de la Serna J
AU - Broichhagen,J
AU - Hodson,DJ
AU - Minnion,J
AU - Rutter,GA
AU - Bloom,SR
AU - Tomas,A
AU - Jones,B
DO - 10.1111/bph.15134
EP - 3923
PY - 2020///
SN - 0007-1188
SP - 3905
TI - Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide.
T2 - British Journal of Pharmacology
UR -
UR -
UR -
UR -
VL - 177
ER -