Fang Zijian, Chen Shiqian, Pickford Philip, Broichhagen Johannes, Hodson David J, Corrêa Ivan R, Kumar Sunil, Görlitz Frederik, Dunsby Chris, French Paul M W, Rutter Guy A, Tan Tricia, Bloom Stephen R, Tomas Alejandra, Jones Ben
Section of Endocrinology and Investigative Medicine, Imperial College London, London, W12 0NN, United Kingdom.
Department Chemical Biology, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, 13125, Germany.
ACS Pharmacol Transl Sci. 2020 Mar 17;3(2):345-360. doi: 10.1021/acsptsci.0c00022. eCollection 2020 Apr 10.
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.
信号偏倚和膜转运最近已成为2型糖尿病和肥胖症中胰高血糖素样肽-1受体（GLP-1R）治疗靶点的重要考虑因素。在本研究中，我们评估了一系列肽，这些肽在天然GLP-1和艾塞那肽-4（已批准的GLP-1R激动剂所基于的原型配体）之间具有不同程度的序列同源性。我们发现，激动剂介导的环磷酸腺苷信号传导、β-抑制蛋白的募集、内吞作用和再循环存在显著差异，这既取决于第1位His→Phe的转换，也取决于两种激动剂的特定中间肽螺旋区域和C末端。这些观察结果与β细胞模型中的胰岛素分泌相关，并为配体因素如何在细胞水平上影响GLP-1R功能提供了见解。
