G Milligan, M Canals, J D Pediani, J Ellis, J F Lopez-Gimenez
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引用次数: 60
Abstract
A wide range of techniques have been employed to examine the quaternary structure of G-protein-coupled receptors (GPCRs). Although it is well established that homo-dimerisation is common, recent studies have sought to explore the physical basis of these interactions and the role of dimerisation in signal transduction. Growing evidence hints at the existence of higher-order organisation of individual GPCRs and the potential for hetero-dimerisation between pairs of co-expressed GPCRs. Here we consider how both homo-dimerisation/oligomerisation and hetero-dimerisation can regulate signal transduction through GPCRs and the potential consequences of this for function of therapeutic medicines that target GPCRs. Hetero-dimerisation is not the sole means by which co-expressed GPCRs may regulate the function of one another. Heterologous desensitisation may be at least as important and we also consider if this can be the basis for physiological antagonism between pairs of co-expressed GPCRs. Although there may be exceptions (Meyer et al. 2006), a great deal of recent evidence has indicated that most G-protein-coupled receptors (GPCRs) do not exist as monomers but rather as dimers or, potentially, within higher-order oligomers (Milligan 2004b; Park et al. 2004). Support for such models has been provided by a range of studies employing different approaches, including co-immunoprecipitation of differentially epitope-tagged but co-expressed forms of the same GPCR, co-operativity in ligand binding and a variety of resonance energy transfer techniques (Milligan and Bouvier 2005). Only for the photon receptor rhodopsin has the organisational structure of a GPCR been studied in situ. The application of atomic force microscopy to murine rod outer segment discs indicated that rhodopsin is organised in a series of parallel arrays of dimers (Liang et al. 2003) and based on this, molecular models were constructed to try to define and interpret regions of contact between the monomers (Fotiadis et al. 2004). Only for relatively few other GPCRs are details of the molecular basis of dimerisation available but within this limited data set, recent studies on the dopamine D2 receptor suggest a means by which information on the binding of an agonist can be transmitted between the two elements of the dimer via the dimer interface (Guo et al. 2005). Although the availability of cDNAs encoding molecularly defined GPCRs has allowed high-throughput screening for ligands that modulate GPCR function, this is performed almost exclusively in heterologous cell lines transfected to express only the specific GPCR of interest. Given that the human genome contains some 400-450 genes encoding non-chemosensory GPCRs, it is clear that any individual cell of the body may express a considerable number of GPCRs. Interactions between these, either via hetero-dimerisation, via heterologous desensitisation or via the integration of downstream signals can potentially alter the pharmacology, sensitivity and function of receptor agonists and hence produce varied responses. In this article, we will use specific examples to consider the role of homo-dimerisation/oligomerisation in GPCR function and whether either direct hetero-dimerisation or heterologous desensitisation between pairs of co-expressed GPCRs affects the function of the receptor pairs.
广泛的技术已经被用来检查g蛋白偶联受体(gpcr)的四级结构。虽然同源二聚化很常见,但最近的研究试图探索这些相互作用的物理基础以及二聚化在信号转导中的作用。越来越多的证据表明,存在单个gpcr的高阶组织,并且在共表达的gpcr对之间存在异二聚化的潜力。在这里,我们考虑了同源二聚化/寡聚化和异二聚化如何通过gpcr调节信号转导,以及这对靶向gpcr的治疗药物功能的潜在影响。异二聚化并不是共表达gpcr调节彼此功能的唯一途径。异源脱敏可能至少同样重要,我们也考虑这是否可以成为共表达gpcr对之间生理拮抗的基础。尽管可能有例外(Meyer et al. 2006),但最近的大量证据表明,大多数g蛋白偶联受体(gpcr)不是作为单体存在,而是作为二聚体存在,或者可能存在于高阶低聚物中(Milligan 2004b;Park et al. 2004)。采用不同方法的一系列研究为这些模型提供了支持,包括对带有不同表位标记但共表达形式的相同GPCR的共免疫沉淀、配体结合的协同性和各种共振能量转移技术(Milligan and Bouvier 2005)。只有对光子受体视紫红质的组织结构进行了原位研究。原子力显微镜在小鼠棒外段圆盘上的应用表明,视紫红质是由一系列平行的二聚体阵列组成的(Liang et al. 2003),并在此基础上构建了分子模型,试图定义和解释单体之间的接触区域(Fotiadis et al. 2004)。只有相对较少的其他gpcr具有二聚化的分子基础细节,但在这有限的数据集中,最近对多巴胺D2受体的研究表明,通过二聚体界面,可以在二聚体的两个元素之间传递激动剂结合的信息(Guo et al. 2005)。虽然编码分子定义的GPCR的cdna的可用性允许高通量筛选调节GPCR功能的配体,但这几乎只在转染仅表达感兴趣的特定GPCR的异源细胞系中进行。鉴于人类基因组包含约400-450个编码非化学感觉gpcr的基因,很明显,人体的任何单个细胞都可能表达相当数量的gpcr。它们之间的相互作用,无论是通过异源二聚化、异源脱敏还是通过下游信号的整合,都可能改变受体激动剂的药理学、敏感性和功能,从而产生不同的反应。在本文中,我们将使用具体的例子来考虑同源二聚化/寡聚化在GPCR功能中的作用,以及共表达GPCR对之间的直接异源二聚化或异源脱敏是否会影响受体对的功能。