The Influence of Peptide Context on Signaling and Trafficking of Glucagon-like Peptide-1 Receptor Biased Agonists
| Autor: | Christopher Dunsby, Paul Michael William French, Stephen R. Bloom, Alejandra Tomas, David J. Hodson, Zijian Fang, Philip Pickford, Guy A. Rutter, Sunil Kumar, Johannes Broichhagen, Shiqian Chen, Ben Jones, Ivan R. Corrêa, Tricia Tan, Frederik Görlitz |
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| Přispěvatelé: | Medical Research Council (MRC), Society for Endocrinology, European Foundation for the Study of Diabetes, Biotechnology and Biological Sciences Research Council (BBSRC), Wellcome Trust |
| Rok vydání: | 2020 |
| Předmět: |
endocrine system
Context (language use) Peptide Type 2 diabetes Therapeutic targeting Endocytosis 03 medical and health sciences 0302 clinical medicine medicine Pharmacology (medical) Insulin secretion Receptor 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences Chemistry Ligand digestive oral and skin physiology medicine.disease Glucagon-like peptide-1 Cell biology Signalling hormones hormone substitutes and hormone antagonists 030217 neurology & neurosurgery Function (biology) |
| Zdroj: | ACS Pharmacology & Translational Science ACS Pharmacol Transl Sci |
| ISSN: | 2575-9108 |
| DOI: | 10.1021/acsptsci.0c00022 |
| Popis: | 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 signalling, endocytosis and recycling, dependent both on the introduction of a His → Phe switch at position 1 and the specific mid-peptide 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.Graphical abstract |
| Databáze: | OpenAIRE |
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