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Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide.
Br J Pharmacol. 2020 May 20 [Online ahead of print]BJ

Abstract

BACKGROUND AND PURPOSE

Amino acid substitutions at the N-termini of glucagon-like peptide-1 (GLP-1) receptor agonist peptides result in distinct patterns of intracellular signalling, sub-cellular trafficking and efficacy in vivo. Here, we to determine whether sequence differences at the ligand C-termini of clinically approved GLP-1 receptor agonists 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 fivefold less potent for cAMP signalling. Both peptides induced extensive GLP-1 receptor clustering in the plasma membrane and were rapidly endocytosed, but the GLP-1 receptor 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-1 receptor trafficking via mechanisms unrelated to GLP-1 receptor occupancy. These differences were associated with changes in their ability to control blood glucose and therefore may be therapeutically relevant.

Authors+Show Affiliations

Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK.Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK.Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK.Section of Cell Biology and Functional Genomics, Imperial College London, London, UK.National Heart and Lung Institute, Imperial College London, London, UK.Department Chemical Biology, Max Planck Institute for Medical Research, Heidelberg, Germany. Department Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany.Institute of Metabolism and Systems Research (IMSR), and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, UK. Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK.Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK.Section of Cell Biology and Functional Genomics, Imperial College London, London, UK.Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK.Section of Cell Biology and Functional Genomics, Imperial College London, London, UK.Section of Endocrinology and Investigative Medicine, Imperial College London, London, UK.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32436216

Citation

Pickford, Philip, et al. "Signalling, Trafficking and Glucoregulatory Properties of Glucagon-like Peptide-1 Receptor Agonists Exendin-4 and Lixisenatide." British Journal of Pharmacology, 2020.
Pickford P, Lucey M, Fang Z, et al. Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide. Br J Pharmacol. 2020.
Pickford, P., Lucey, M., Fang, Z., Bitsi, S., de la Serna, J. B., Broichhagen, J., Hodson, D. J., Minnion, J., Rutter, G. A., Bloom, S. R., Tomas, A., & Jones, B. (2020). Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide. British Journal of Pharmacology. https://doi.org/10.1111/bph.15134
Pickford P, et al. Signalling, Trafficking and Glucoregulatory Properties of Glucagon-like Peptide-1 Receptor Agonists Exendin-4 and Lixisenatide. Br J Pharmacol. 2020 May 20; PubMed PMID: 32436216.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide. AU - Pickford,Philip, AU - Lucey,Maria, AU - Fang,Zijian, AU - Bitsi,Stavroula, AU - de la Serna,Jorge Bernardino, AU - Broichhagen,Johannes, AU - Hodson,David J, AU - Minnion,James, AU - Rutter,Guy A, AU - Bloom,Stephen R, AU - Tomas,Alejandra, AU - Jones,Ben, Y1 - 2020/05/20/ PY - 2019/10/13/received PY - 2020/04/22/revised PY - 2020/04/28/accepted PY - 2020/5/22/pubmed PY - 2020/5/22/medline PY - 2020/5/22/entrez JF - British journal of pharmacology JO - Br. J. Pharmacol. N2 - BACKGROUND AND PURPOSE: Amino acid substitutions at the N-termini of glucagon-like peptide-1 (GLP-1) receptor agonist peptides result in distinct patterns of intracellular signalling, sub-cellular trafficking and efficacy in vivo. Here, we to determine whether sequence differences at the ligand C-termini of clinically approved GLP-1 receptor agonists 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 fivefold less potent for cAMP signalling. Both peptides induced extensive GLP-1 receptor clustering in the plasma membrane and were rapidly endocytosed, but the GLP-1 receptor 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-1 receptor trafficking via mechanisms unrelated to GLP-1 receptor occupancy. These differences were associated with changes in their ability to control blood glucose and therefore may be therapeutically relevant. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/32436216/Signalling,_trafficking_and_glucoregulatory_properties_of_glucagon-like_peptide-1_receptor_agonists_exendin-4_and_lixisenatide L2 - https://doi.org/10.1111/bph.15134 DB - PRIME DP - Unbound Medicine ER -
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