期刊
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
卷 3, 期 2, 页码 345-360出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.0c00022
关键词
GLP-1R; exendin-4; biased signaling; membrane trafficking; endocytosis; recycling
资金
- MRC [MR/N00275X/1, MR/S025618/1, MR/R022259/1, MR/J0003042/1, MR/L020149/1]
- EFSD/Boehringer Ingelheim European Research Programme on Multi-System Challenges in Diabetes
- BBSRC
- NIHR Biomedical Research Centre Funding Scheme
- Academy of Medical Sciences
- EPSRC
- Diabetes UK [BDA/11/0004210, BDA/15/0005275, BDA 16/0005485, 17/0005681]
- European Research Council (ERC) under the European Union [715884]
- Wellcome Trust [212625/Z/18/Z]
- European Union's Horizon 2020 research and innovation programme via the Innovative Medicines Initiative 2 Joint Undertaking [115881]
- EuroCHIP grant [FP7-HEALTH-2009-241592]
- NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award
- Society for Endocrinology
- BBSRC [BB/M006786/1, BB/J015873/1] Funding Source: UKRI
- MRC [MR/K001981/1, MR/K023667/1, MR/R010676/1, MR/M012646/1, MR/L020149/1, 1854365, MR/L02036X/1, MR/R022259/1, MR/N00275X/1, MR/S025618/1, MR/N020472/1] Funding Source: UKRI
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 cyclic AMP signaling, recruitment of beta-arrestins, endocytosis, and recycling, dependent both on the introduction of a His -> Phe switch at position 1 and the specific midpeptide 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.
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