G蛋白偶联受体二聚化在药物开发中所发挥的特异性作用

doi:10.5246/jcps.2011.06.068

G蛋白偶联受体二聚化在药物开发中所发挥的特异性作用

蔡欣, 陈京, 白波^*

1. 泰山医学院基础医学部神经生物学, 山东泰安 271000
2. 济宁医学院神经生物研究所, 山东济宁 272000
3. 英国华威大学华威医学院, 英国 999020

收稿日期:2011-04-06 修回日期:2011-09-10 出版日期:2011-11-15 发布日期:2011-11-15
通讯作者: 白波*

Exploring the specific role of GPCRs dimerization in drug discovery

Xin Cai, Jing Chen, Bo Bai^*

1. Department of Preclinical Medicine, Taishan Medical University, Tai'an 271000, China
2. Neurobiology Institute, Jining Medical University, Jining 272000, China
3. Warwick Medical School,University of Warwick, England 999020, United Kingdom

Received:2011-04-06 Revised:2011-09-10 Online:2011-11-15 Published:2011-11-15
Contact: Bo Bai*

摘要/Abstract

摘要：

G蛋白偶联受体 (GPCRs) 是与G蛋白相偶联的七次跨膜受体, 其成员有上千种, 是重要的药物靶点之一。目前, GPCRs相关药物占市场上药物的40%-50%。在过去的十年中, 对GPCRs主要以单体的形式存在着的这一假说做出了重新评估, 大量事实证明GPCRs也能以同源或异源二聚体, 甚至是高阶寡聚体的形式存在, 比较热门的领域是GPCRs二聚化。最近研究表明同源或异源二聚化有不同于单体的特异功能特征, 包括配体识别、信号转导、运输等。同时, 在较少副作用治疗疾病的新药开发上, 具有不同病理和信号转导途径的二聚体的出现开辟了新的领域。本综述主要介绍二聚体的特异结构及其特异的信号转导途径, 从而有助于在GPCRs药物开发中取得丰硕的成果。

关键词: G蛋白偶联受体, 二聚化, 信号转导, 药物开发

Abstract:

G-protein-coupled receptors (GPCRs) are G-protein-coupled heptaspanning-membrane receptors. This group has thousands of members and is one of the important drug targets, accounting for 40%-50% of the drugs currently on the market. In the last decade, there has been a substantial re-evaluation of the assumption that GPCRs exist primarily as monomeric polypeptides, with support increasing for a model in which GPCRs can exist as homo- or hetero- dimers or even high-order oligomers. GPCRs dimers are hot research topics. Recent reports suggest that homo- or hetero- dimers exhibit "specific" functional properties which are distinct from monomeric receptors, involving agonist recognition, signaling, trafficking, and so on. Meanwhile, the occurrence of dimers with different pharmacological and signaling properties opens a completely new field in the search for novel drug targets useful to combat a variety of diseases and with potentially fewer side effects. In this paper, we will mainly review their specific structures and signal transduction, which help us reach for the high-hanging fruits in GPCRs drug discovery.

Key words: G-protein-coupled receptors, Receptor dimers, Signal transduction, Drug discovery

中图分类号:

R915

Supporting: Foundation items: National Natural Science Foundation of China (Grant No. 30971081, 30870932, and 81070961), Shandong Provincial Natural Science Foundation (Grant No. Y2007D01 and ZR2009DZ004).
^*Corresponding author. Tel.: 86-537-3616002; Fax: 86-537-3616777

蔡欣, 陈京, 白波^*. G蛋白偶联受体二聚化在药物开发中所发挥的特异性作用[J]. , DOI: 10.5246/jcps.2011.06.068.

Xin Cai, Jing Chen, Bo Bai^*. Exploring the specific role of GPCRs dimerization in drug discovery[J]. , DOI: 10.5246/jcps.2011.06.068.

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