التفاصيل البيبلوغرافية
| العنوان: |
Signalling, trafficking and glucoregulatory properties of glucagon-like peptide-1 receptor agonists exendin-4 and lixisenatide. |
| المؤلفون: |
Pickford, Philip, Lucey, Maria, Fang, Zijian, Bitsi, Stavroula, Serna, Jorge Bernardino, Broichhagen, Johannes, Hodson, David J., Minnion, James, Rutter, Guy A., Bloom, Stephen R., Tomas, Alejandra, Jones, Ben, de la Serna, Jorge Bernardino |
| المصدر: |
British Journal of Pharmacology; Sep2020, Vol. 177 Issue 17, p3905-3923, 19p, 1 Chart, 7 Graphs |
| مصطلحات موضوعية: |
GLUCAGON-like peptide-1 agonists, GLUCOMANNAN, GLUCAGON-like peptide-1 receptor, BLOOD sugar, TRAFFIC signs & signals, CELL membranes, AMINO acids |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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