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The Influence of Peptide Context on Signaling and Trafficking of Glucagon-like Peptide-1 Receptor Biased Agonists.
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-03-17 , DOI: 10.1021/acsptsci.0c00022 Zijian Fang 1 , Shiqian Chen 1 , Philip Pickford 1 , Johannes Broichhagen 2 , David J Hodson 3, 4 , Ivan R Corrêa 5 , Sunil Kumar 6 , Frederik Görlitz 6 , Chris Dunsby 6 , Paul M W French 6 , Guy A Rutter 7 , Tricia Tan 1 , Stephen R Bloom 1 , Alejandra Tomas 7 , Ben Jones 1
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-03-17 , DOI: 10.1021/acsptsci.0c00022 Zijian Fang 1 , Shiqian Chen 1 , Philip Pickford 1 , Johannes Broichhagen 2 , David J Hodson 3, 4 , Ivan R Corrêa 5 , Sunil Kumar 6 , Frederik Görlitz 6 , Chris Dunsby 6 , Paul M W French 6 , Guy A Rutter 7 , Tricia Tan 1 , Stephen R Bloom 1 , Alejandra Tomas 7 , Ben Jones 1
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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 β-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.
中文翻译：
肽背景对胰高血糖素样肽 1 受体偏向激动剂信号传导和运输的影响。
信号偏差和膜运输最近已成为 2 型糖尿病和肥胖症胰高血糖素样肽 1 受体 (GLP-1R) 治疗靶向的重要考虑因素。在本研究中，我们评估了天然 GLP-1 和 exendin-4 之间具有不同序列同源性的肽系列，exendin-4 是已批准的 GLP-1R 激动剂所基于的原型配体。我们发现激动剂介导的环 AMP 信号传导、β-抑制蛋白的募集、内吞作用和再循环方面存在显着差异，这取决于在位置 1 引入 His → Phe 开关以及两者的特定中肽螺旋区域和 C 末端激动剂。这些观察结果与 β 细胞模型中的胰岛素分泌有关，并提供了配体因子如何在细胞水平影响 GLP-1R 功能的见解。
更新日期：2020-04-23
中文翻译：
肽背景对胰高血糖素样肽 1 受体偏向激动剂信号传导和运输的影响。
信号偏差和膜运输最近已成为 2 型糖尿病和肥胖症胰高血糖素样肽 1 受体 (GLP-1R) 治疗靶向的重要考虑因素。在本研究中，我们评估了天然 GLP-1 和 exendin-4 之间具有不同序列同源性的肽系列，exendin-4 是已批准的 GLP-1R 激动剂所基于的原型配体。我们发现激动剂介导的环 AMP 信号传导、β-抑制蛋白的募集、内吞作用和再循环方面存在显着差异，这取决于在位置 1 引入 His → Phe 开关以及两者的特定中肽螺旋区域和 C 末端激动剂。这些观察结果与 β 细胞模型中的胰岛素分泌有关，并提供了配体因子如何在细胞水平影响 GLP-1R 功能的见解。
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