药学学报, 2019, 54(1): 66-72
引用本文:
殷琳, 陈熙, 杨秀颖, 杜冠华. 偏向β-抑制蛋白的GPCR信号传导机制及药物研究进展[J]. 药学学报, 2019, 54(1): 66-72.
YIN Lin, CHEN Xi, YANG Xiu-ying, DU Guan-hua. Mechanisms of β-arrestin-biased GPCR signal transduction and advances in drug research[J]. Acta Pharmaceutica Sinica, 2019, 54(1): 66-72.

偏向β-抑制蛋白的GPCR信号传导机制及药物研究进展
殷琳, 陈熙, 杨秀颖, 杜冠华
中国医学科学院、北京协和医学院, 药物研究所药物靶点研究与新药筛选北京市重点实验室, 北京 100050
摘要:
G蛋白偶联受体(G protein-coupled receptors,GPCR)是一类存在于细胞膜表面的受体超家族。随着对GPCR脱敏调节器β-抑制蛋白(β-arrestin)研究的深入,发现GPCRs激活后不仅能通过G蛋白依赖途径进行信号的传导,也能通过非G蛋白依赖途径,即β-抑制蛋白通路来调节受体内吞和脱敏,甚至启动一波新的信号传导,由此提出"偏向性传导"的概念,即配体激活受体后能够选择性激活相应的信号通路,使信号沿着特定"偏好"的下游通路继续向下传导,并将与受体结合后能引起偏向性激活的配体称为"偏向性配体"。一般认为,偏向性的产生是因为配体与受体结合方式存在差别,包括受体构象的差异、下游信号蛋白结合位点的差异以及信号蛋白自身构象的差异等。本文就偏向β-抑制蛋白的GPCR信号传导机制以及偏向β-抑制蛋白通路的配体类药物研究进展做一简要综述。
关键词:    G蛋白偶联受体      β-抑制蛋白      偏向性机制      偏向性计算方法      偏向性配体药物     
Mechanisms of β-arrestin-biased GPCR signal transduction and advances in drug research
YIN Lin, CHEN Xi, YANG Xiu-ying, DU Guan-hua
Beijing Key Laboratory of Drug Target Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
G protein-coupled receptors (GPCR) are a class of receptor superfamily that exist on the surface of cell membrane. With the intensive studies on the GPCR desensitization regulator-β-arrestins, it is found that activated GPCR can not only conduct signal transduction through G protein-dependent pathway, but also mediate via non-G protein-dependent pathway. In addition to mediate endocytosis and desensitization, β-arrestins also initiate a new series of signal transduction events. Therefore, the concept of "biased transduction" was put forward:the receptor activated by a specific ligand could selectively activate a specific signaling pathway, leading the signal to be transmitted downstream along a "preferential" pathway. We call the ligand that binds to the receptor and causes biased activation "biased ligand". It is generally believed that the phenomenon of bias results from different binding modes of ligands and receptors, including multiple receptor conformations, diverse sites that downstream signal proteins bind, and signal proteins' own conformations, etc. Here we give a brief review focusing on the mechanisms of β-arrestin-biased GPCR signal transduction and the advances in the drug development on β-arrestin biased ligands.
Key words:    G protein-coupled receptor    β-arrestin    mechanism of bias    bias calculation method    biased ligand drug   
收稿日期: 2018-07-03
DOI: 10.16438/j.0513-4870.2018-0610
基金项目: 国家自然科学基金资助项目(81470159,81770847);中国医学科学院创新工程重大协同创新项目(2016-I2M-3-007,2017-I2M-1-010).
通讯作者: 杨秀颖,Tel:86-10-63165313,E-mail:lucia@imm.ac.cn;杜冠华,Tel:86-10-63165184,E-mail:dugh@imm.ac.cn
Email: lucia@imm.ac.cn;dugh@imm.ac.cn
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