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首页> 外文期刊>Biochemical Pharmacology >Glucagon-like peptide-1 receptor internalisation controls spatiotemporal signalling mediated by biased agonists
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Glucagon-like peptide-1 receptor internalisation controls spatiotemporal signalling mediated by biased agonists

机译：胰高血糖素样肽-1受体内化控制由偏置激动剂介导的时尚信号传导

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The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target in the treatment of type 2 diabetes due to its roles in regulating blood glucose and in promoting weight loss. Like many GPCRs, it is pleiotropically coupled, can be activated by multiple ligands and is subject to biased agonism. The GLP-1R undergoes agonist mediated receptor internalisation that may be associated with spatiotemporal control of signalling and biased agonism, although to date, this has not been extensively explored. Here, we investigate GLP-1R trafficking and its importance with regard to signalling, including the localisation of key signalling molecules, mediated by biased peptide agonists that are either endogenous GLP-1R ligands or are used clinically. Each of the agonists promoted receptor internalisation through a dynamin and caveolae dependent mechanism and traffic the receptor to both degradative and recycling pathways. This internalisation is important for signalling, with cAMP and ERK1/2 phoshorylation (pERK1/2) generated by both plasma membrane localised and internalised receptors. Further assessment of pERK1/2 revealed that all peptides induced nuclear ERK activity, but ligands, liraglutide and oxyntomodulin that are biased towards pERK1/2 relative to cAMP (when compared to GLP-1 and exendin-4), also stimulated pERK1/2 activity in the cytosol. This compartmentalisation of ERK1/2 signalling was reliant on receptor internalisation, with restriction of receptor localisation to the plasma membrane limiting ERK1/2 signalling to the cytosol. Thus, this study implicates a role of receptor internalisation in spatiotemporal control of ERK1/2 signalling that may contribute to GLP-1R biased agonism.
机译：胰高血糖素样肽-1受体（GLP-1R）是治疗2型糖尿病的主要治疗靶标，因为其作用在调节血糖和促进体重减轻时。与许多GPCR一样，它是脂肪耦合的，可以由多个配体激活并且受到偏置激动的影响。 GLP-1R经历激动剂介导的受体内化，其可能与信号传导和偏见激动主义的时尚控制相关，尽管迄今为止，这尚未得到广泛探索。在这里，我们调查GLP-1R贩运的GLP-1R贩运及其重要性，包括通过均匀的GLP-1R配体或临床使用的偏置肽激动剂介导的键信号分子的定位。每种激动剂通过动力学和Caveolae依赖机制促进受体内化，并将受体交通给降解和再循环途径。这种内化对于信号传导至重要的是信号，营养阵营和ERK1 / 2骨盆（PERK1 / 2）由质膜局部化和内化受体产生。进一步评估Perk1 / 2揭示了所有肽诱导的核ERK活性，但是与营地相对于营地（与GLP-1和EXENDIN-4相比）偏向PERK1 / 2的配体，林蛙和氧化脲素，还刺激了PERK1 / 2活性在细胞溶胶中。 ERK1 / 2信号传导的这种隔间化依赖于受体内化，限制受体定位对血浆膜限制ERK1 / 2信号传导至细胞溶胶。因此，该研究意味着受体内化在可能导致GLP-1R偏向激动的时尚控制的时尚控制中的作用。

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