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Distinct roles of the extracellular surface residues of glucagon-like peptide-1 receptor in B-arrestin 1/2 signaling

文献类型：期刊论文

作者Lei, Saifei1,9; Meng, Qian8; Liu, Yanyun7; Liu, Qiaofeng6; Dai, Antao9; Cai, Xiaoqing9; Wang, Ming- Wei2,3,4,5; Zhou, Qingtong4,5; Zhou, Hu8; Yang, Dehua4,7,8,9
刊名EUROPEAN JOURNAL OF PHARMACOLOGY
出版日期2024-04-05
卷号968页码:17
关键词GLP-1R B-arrestin 1/2 Biased agonism Bioluminescence resonance energy transfer Proteomics profiling
ISSN号0014-2999
DOI10.1016/j.ejphar.2024.176419
通讯作者Zhou, Qingtong(zhouqt@fudan.edu.cn) ; Zhou, Hu(zhouhu@simm.ac.cn) ; Yang, Dehua(dhyang@simm.ac.cn)
英文摘要Glucagon-like peptide-1 receptor (GLP-1R) is a prime drug target for type 2 diabetes and obesity. The ligand initiated GLP-1R interaction with G protein has been well studied, but not with B -arrestin 1/2. Therefore, bioluminescence resonance energy transfer (BRET), mutagenesis and an operational model were used to evaluate the roles of 85 extracellular surface residues on GLP-1R in B -arrestin 1/2 recruitment triggered by three representative GLP-1R agonists (GLP-1, exendin-4 and oxyntomodulin). Residues selectively regulated B -arrestin 1/2 recruitment for diverse ligands, and B -arrestin isoforms were identified. Mutation of residues K130 -S136, L142 and Y145 on the transmembrane helix 1 (TM1)-extracellular domain (ECD) linker decreased B -arrestin 1 recruitment but increased B -arrestin 2 recruitment. Other extracellular loop (ECL) mutations, including P137A, Q211A, D222A and M303A selectively affected B -arrestin 1 recruitment while D215A, L217A, Q221A, S223A, Y289A, S301A, F381A and I382A involved more in B -arrestin 2 recruitment for the ligands. Oxyntomodulin engaged more broadly with GLP-1R extracellular surface to drive B -arrestin 1/2 recruitment than GLP-1 and exendin-4; I147, W214 and L218 involved in B -arrestin 1 recruitment, while L141, D215, L218, D293 and F381 in B -arrestin 2 recruitment for oxyntomodulin particularly. Additionally, the non-conserved residues on B -arrestin 1/2 C-domains contributed to interaction with GLP-1R. Further proteomic profiling of GLP-1R stably expressed cell line upon ligand stimulation with or without B -arrestin 1/2 overexpression demonstrated both commonly and biasedly regulated proteins and pathways associated with cognate ligands and B-arrestins. Our study offers valuable information about ligand induced B -arrestin recruitment mediated by GLP-1R and consequent intracellular signaling events.
WOS关键词GLP-1 RECEPTOR ; OPERATIONAL MODEL ; ERK1/2 ACTIVATION ; BETA ; BINDING ; LOOP ; INTERNALIZATION ; BETA-ARRESTIN2 ; TRAFFICKING ; MECHANISMS
资助项目National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[21704064] ; National Key Basic Research Program of China[2018ZX09735-001] ; National Key Basic Research Program of China[2018ZX09711002-002-005] ; National Key Basic Research Program of China[2021ZD0203400] ; Hainan Provincial Major Science and Tech-nology Project[2018YFA0507000] ; Hainan Provincial Major Science and Tech-nology Project[2022YFA1302902] ; [ZDKJ2021028] ; [21JC1401600]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001198990100001
出版者ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/310777]  
专题新药研究国家重点实验室
通讯作者Zhou, Qingtong; Zhou, Hu; Yang, Dehua
作者单位1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China
2.Hainan Med Univ, Sch Pharm, Haikou 570228, Peoples R China
3.Univ Tokyo, Sch Sci, Dept Chem, Tokyo 1130033, Japan
4.Res Ctr Deepsea Bioresources, Sanya 572025, Hainan, Peoples R China
5.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China
6.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China
7.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
9.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Lei, Saifei,Meng, Qian,Liu, Yanyun,et al. Distinct roles of the extracellular surface residues of glucagon-like peptide-1 receptor in B-arrestin 1/2 signaling[J]. EUROPEAN JOURNAL OF PHARMACOLOGY,2024,968:17.
APA Lei, Saifei.,Meng, Qian.,Liu, Yanyun.,Liu, Qiaofeng.,Dai, Antao.,...&Yang, Dehua.(2024).Distinct roles of the extracellular surface residues of glucagon-like peptide-1 receptor in B-arrestin 1/2 signaling.EUROPEAN JOURNAL OF PHARMACOLOGY,968,17.
MLA Lei, Saifei,et al."Distinct roles of the extracellular surface residues of glucagon-like peptide-1 receptor in B-arrestin 1/2 signaling".EUROPEAN JOURNAL OF PHARMACOLOGY 968(2024):17.

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来源：上海药物研究所

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