期刊
PLOS BIOLOGY
卷 17, 期 8, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.3000097
关键词
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资金
- MRC project [MR/R010676/1]
- Wellcome Trust
- Society for Endocrinology
- Academy of Medical Sciences
- MRC
- BBSRC
- NIHR
- Integrative Mammalian Biology (IMB) Capacity Building Award
- EuroCHIP grant [FP7-HEALTH-2009241592]
- NIHR Biomedical Research Centre funding scheme
- MRC [MR/P01870X/1, MR/R022259/1, MR/R010676/1, MR/K023667/1] Funding Source: UKRI
The glucagon-like peptide-1 receptor (GLP-1R), a key pharmacological target in type 2 diabetes (T2D) and obesity, undergoes rapid endocytosis after stimulation by endogenous and therapeutic agonists. We have previously highlighted the relevance of this process in fine-tuning GLP-1R responses in pancreatic beta cells to control insulin secretion. In the present study, we demonstrate an important role for the translocation of active GLP-1Rs into liquid-ordered plasma membrane nanodomains, which act as hotspots for optimal coordination of intracellular signaling and clathrin-mediated endocytosis. This process is dynamically regulated by agonist binding through palmitoylation of the GLP-1R at its carboxyl-terminal tail. Biased GLP-1R agonists and small molecule allosteric modulation both influence GLP-1R palmitoylation, clustering, nanodomain signaling, and internalization. Downstream effects on insulin secretion from pancreatic beta cells indicate that these processes are relevant to GLP-1R physiological actions and might be therapeutically targetable.
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