Smit Martine J, Vischer Henry F, Bakker Remko A, Jongejan Aldo, Timmerman Henk, Pardo Leonardo, Leurs Rob
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Vrije Universiteit, Faculty of Sciences, Department of Chemistry, 1081 HV Amsterdam, The Netherlands.
Annu Rev Pharmacol Toxicol. 2007;47:53-87. doi: 10.1146/annurev.pharmtox.47.120505.105126.
G protein-coupled receptors (GPCRs) respond to a chemically diverse plethora of signal transduction molecules. The notion that GPCRs also signal without an external chemical trigger, i.e., in a constitutive or spontaneous manner, resulted in a paradigm shift in the field of GPCR pharmacology. The discovery of constitutive GPCR activity and the fact that GPCR binding and signaling can be strongly affected by a single point mutation drew attention to the evolving area of GPCR pharmacogenomics. For a variety of GPCRs, point mutations have been convincingly linked to human disease. Mutations within conserved motifs, known to be involved in GPCR activation, might explain the properties of some naturally occurring, constitutively active GPCR variants linked to disease. In this review, we provide a brief historical introduction to the concept of constitutive receptor activity and the pharmacogenomic and structural aspects of constitutive receptor activity.
G蛋白偶联受体（GPCRs）可对大量化学性质各异的信号转导分子作出反应。GPCRs也能在没有外部化学触发因素的情况下发出信号，即以组成性或自发性方式发出信号，这一观点导致了GPCR药理学领域的范式转变。组成性GPCR活性的发现，以及GPCR结合和信号传导可受到单点突变强烈影响这一事实，引发了人们对GPCR药物基因组学这一不断发展领域的关注。对于多种GPCR而言，单点突变已被确凿地证明与人类疾病有关。已知参与GPCR激活的保守基序内的突变，可能解释了一些与疾病相关的天然存在的组成性激活GPCR变体的特性。在这篇综述中，我们简要介绍了组成性受体活性这一概念的历史，以及组成性受体活性的药物基因组学和结构方面的内容。
