@article{Pickford:2020:10.1111/bph.15134,
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 = {http://dx.doi.org/10.1111/bph.15134},
volume = {177},
year = {2020}
}

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TY  - JOUR
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  - http://dx.doi.org/10.1111/bph.15134
UR  - https://www.ncbi.nlm.nih.gov/pubmed/32436216
UR  - https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.15134
UR  - http://hdl.handle.net/10044/1/79474
VL  - 177
ER  - 

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