Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells
Agonist-induced membrane nanodomain clustering drives GLP-1 receptor responses in pancreatic beta cells
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DOI：
10.1371/journal.pbio.3000097
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发表时间：
2019-08-01
期刊：
影响因子：
9.8
通讯作者：
Tomas, Alejandra
中科院分区：
文献类型：
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作者：
Buenaventura, Teresa;Bitsi, Stavroula;Tomas, Alejandra
胰高血糖素样肽-1受体（GLP-1 R）是2型糖尿病（T2 D）和肥胖症的关键药理学靶点，在内源性和治疗性激动剂刺激后发生快速内吞作用。我们之前已经强调了该过程在胰腺β细胞中微调GLP-1 R反应以控制胰岛素分泌的相关性。在本研究中，我们证明了活性GLP-1 R易位到液体有序质膜纳米结构域中的重要作用，这些纳米结构域作为细胞内信号传导和网格蛋白介导的内吞作用的最佳协调的热点。该过程通过GLP-1 R羧基末端尾部的棕榈酰化受激动剂结合的动态调节。偏倚GLP-1 R激动剂和小分子变构调节均影响GLP-1 R棕榈酰化、成簇、纳米结构域信号传导和内化。对胰腺β细胞胰岛素分泌的下游影响表明，这些过程与GLP-1 R生理作用相关，可能具有治疗靶向性。
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.