G-protein-coupled receptor heteromers:: function and ligand pharmacology
G-protein-coupled receptor heteromers:: function and ligand pharmacology
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DOI：
10.1038/sj.bjp.0707571
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发表时间：
2008-03-01
影响因子：
7.3
通讯作者：
Canela, Ei
中科院分区：
文献类型：
--
作者：
Franco, R.;Casado, V.;Canela, Ei
几乎所有现有的G蛋白偶联受体（GPCR）模型都是基于单体的出现。最近的研究表明，许多GPCR是二聚体。因此，对于一些受体，二聚体而不是单体是与激素/神经递质/药物相互作用的主要物质。假设受体二聚体是单体，则对与受体二聚体拟合的数据解释不明确是有原因的。使用基于二聚体的模型拟合数据不仅给出了与受体二聚体的高亲和力和低亲和力结合的平衡解离常数，而且还给出了反映二聚体内单体之间的分子通信的“协同性指数”。二聚体协同性指数（DC）是一个有价值的工具，能够解释和量化，例如，变构调节剂的作用。对于不同的受体，异聚化赋予受体异聚体特定的功能特性，其可以被认为是“二聚体指纹”。具有不同药理学和信号传导特性的异聚体的出现开辟了一个全新的领域，以寻找可用于对抗各种疾病并可能具有更少副作用的新型药物靶标。拮抗剂是非常常见的靶向GPCR的市售药物，当给定受体与不同的异聚体配偶体一起表达时，拮抗剂显示出可变的亲和力。在开发新药时应考虑到这一事实。
Almost all existing models for G-protein-coupled receptors ( GPCRs) are based on the occurrence of monomers. Recent studies show that many GPCRs are dimers. Therefore for some receptors dimers and not monomers are the main species interacting with hormones/neurotransmitters/drugs. There are reasons for equivocal interpretations of the data fitting to receptor dimers assuming they are monomers. Fitting data using a dimer-based model gives not only the equilibrium dissociation constants for high and low affinity binding to receptor dimers but also a 'cooperativity index' that reflects the molecular communication between monomers within the dimer. The dimer cooperativity index ( DC) is a valuable tool that enables to interpret and quantify, for instance, the effect of allosteric regulators. For different receptors heteromerization confers a specific functional property for the receptor heteromer that can be considered as a 'dimer fingerprint'. The occurrence of heteromers with different pharmacological and signalling properties opens a complete new field to search for novel drug targets useful to combat a variety of diseases and potentially with fewer side effects. Antagonists, which are quite common marketed drugs targeting GPCRs, display variable affinities when a given receptor is expressed with different heteromeric partners. This fact should be taken into account in the development of new drugs.