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G蛋白耦联受体信号转导的偏向性调控及其机制研究进展

翟培彬, 马兰, 刘星^*

复旦大学基础医学院药理研究中心，上海 200032

摘要

G蛋白耦联受体(G protein-coupled receptors, GPCR)被激活后信号可以经G蛋白或β-arrestin向下游传递，并且受体被激活后，由β-arrestin和G蛋白介导的胞内信号传递存在偏向性(signal bias)。这些发现使得GPCR的信号传递体系被重新认识和定义。配体和受体结合位点的细微差异被认为是这一现象产生的关键原因。现有假说认为，不同配体诱导的受体激活态构象也有不同，并由此导致胞内C末端磷酸化位点的不同。磷酸化位点差别最终决定了下游信号传递的走向。偏向性调控现象在GPCR受体家族中并不罕见，其与细胞的许多关键生理功能的精细调控密切相关。利用偏向性调控特点，有可能在减少GPCR靶点相关性副作用的同时，保留其药理学作用，这为GPCR相关的药物开发带来全新思路。

关键词： G蛋白耦联受体; β-arrestin; GPCR偏向性信号通路

分类号：Q71；R915

[Research progress in signal bias of G protein-coupled receptor and its mechanism.] [Article in Chinese]

ZHAI Pei-Bin, MA Lan, LIU Xing^*

Pharmacology Research Center, Shanghai Medical College, Fudan University, Shanghai 200032, China

Abstract

G protein-coupled receptors (GPCRs) mediate signal transduction via G protein or β-arrestin. Several biased ligands and receptors that preferentially signal through either G protein- or β-arrestin-mediated pathways have been identified. These discoveries have redefined the classical GPCR signaling paradigm. Distinct ligand-receptor binding sites might be one of the main reasons for biased signal transduction. It is posited that multiple active conformations of receptors lead to distinct kinase phosphorylation patterns on C terminus of receptors. Phosphorylation patterns decide which signal pathway will be transduced. The biased signal pathway transduction has been found in more than 40 GPCRs till now. A few of them have been found involved in fine-regulation of physiological processes. However, most others still need further investigation. The biased ligands may be developed as tools for understanding the basic physiology of GPCR, and, potentially and most importantly, as fine-tuned therapeutics that maximize beneficial effects and minimize adverse or unwanted effects. These studies will provide new insights into new drug discovery.

Key words: G protein-coupled receptors; β-arrestin; biased GPCR signaling

收稿日期：2016-04-08　　录用日期：2016-06-29

通讯作者：刘星　　E-mail: xingliu@fudan.edu.cn

引用本文：

翟培彬, 马兰, 刘星. G蛋白耦联受体信号转导的偏向性调控及其机制研究进展[J]. 生理学报 2016; 68 (6): 790-798.

ZHAI Pei-Bin, MA Lan, LIU Xing. [Research progress in signal bias of G protein-coupled receptor and its mechanism.] [Article in Chinese]. Acta Physiol Sin 2016; 68 (6): 790-798 (in Chinese with English abstract).