Maudsley Stuart, Martin Bronwen, Luttrell Louis M
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Gerontology Research Center, Johns Hopkins Medical Center, Baltimore, MD 21224, USA.
Curr Alzheimer Res. 2007 Feb;4(1):3-19. doi: 10.2174/156720507779939850.
The manipulation of transmembrane signaling by G protein-coupled receptors (GPCRs) constitutes perhaps the single most important therapeutic target in medicine. Therapeutics acting on GPCRs have traditionally been classified as agonists, partial agonists, or antagonists based on a two state model of receptor function embodied in the ternary complex model. Over the past decade, however, many lines of investigation have shown that GPCR signaling exhibits greater diversity and 'texture' than previously appreciated. Signal diversity arises from numerous factors, among them the ability of receptors to adopt multiple 'active' states with different effector coupling profiles, the formation of receptor dimers that exhibit unique pharmacology, signaling, and trafficking, the dissociation of receptor 'activation' from desensitization and internalization, and the discovery that non-G protein effectors mediate some aspects of GPCR signaling. At the same time, clustering of GPCRs with their downstream effectors in membrane microdomains, and interactions between receptors and a plethora of multidomain scaffolding proteins and accessory/chaperone molecules confers signal preorganization, efficiency, and specificity. More importantly it is likely that alteration in the interactions of these proteins with GPCRs may occur in aging or neurodegenerative disorders, thus defining a distinct 'pharmacology' from that seen in young organisms or normal physiology. In this context, the concept of agonist selective trafficking of receptor signaling, which recognizes that a bound ligand may select between a menu of 'active' receptor conformations and induce only a subset of the possible response profile, presents the opportunity to develop drugs that change the quality as well as the quantity of efficacy and enhance these qualities for specific disorders or other paradigms. As a more comprehensive understanding of the complexity of GPCR signaling is developed, the rational design of ligands possessing increased specific efficacy and attenuated side effects may become the standard mode of drug development.
G蛋白偶联受体（GPCRs）对跨膜信号传导的调控可能是医学中最重要的单一治疗靶点。传统上，作用于GPCRs的治疗药物根据三元复合物模型中体现的受体功能二态模型被分类为激动剂、部分激动剂或拮抗剂。然而，在过去十年中，许多研究表明，GPCR信号传导表现出比以前认识到的更大的多样性和“复杂性”。信号多样性源于众多因素，其中包括受体能够采用具有不同效应器偶联特征的多种“活性”状态、形成具有独特药理学、信号传导和运输特性的受体二聚体、受体“激活”与脱敏和内化的解离，以及发现非G蛋白效应器介导GPCR信号传导的某些方面。同时，GPCRs与其下游效应器在膜微区中的聚集，以及受体与大量多结构域支架蛋白和辅助/伴侣分子之间的相互作用赋予了信号预组织、效率和特异性。更重要的是，这些蛋白质与GPCRs相互作用的改变可能发生在衰老或神经退行性疾病中，从而定义了一种与年轻生物体或正常生理学中所见不同的“药理学”。在这种背景下，受体信号传导的激动剂选择性运输概念认识到结合的配体可以在一系列“活性”受体构象中进行选择，并仅诱导可能反应谱的一个子集，这为开发能够改变疗效质量和数量并针对特定疾病或其他范例增强这些质量的药物提供了机会。随着对GPCR信号传导复杂性的更全面理解的发展，设计具有更高特异性疗效和更低副作用的配体可能会成为药物开发的标准模式。
