两篇Nature :识别重要的信号分子β-arrestins,为疼痛治疗提供新策略
2016/03/29
发表在Nature 上的两篇文章都提供了对一个”信号分子”工作的深入了解,这将为药物在疼痛治疗领域提供新的策略。


发表在Nature 上的两篇文章都提供了对一个”信号分子”工作的深入了解,这将为药物在疼痛治疗领域提供新的策略。

3月23日在线发表在Nature上的研究,是由德国的Würzburg大学和英国的Glasgow大学发现β-arrestins是个由G蛋白偶联受体(GPCRs)激活的独立信号分子。在同一天的Nature,美国的SouthCarolina医科大学的研究小组人员用不同的技术得出了相似的结论。

G蛋白偶联受体是药物研究的重要目标,是包括疼痛和知觉感受的至关重要的细胞通讯过程。作为很多治疗药物的分子靶点,G蛋白偶联受体被认为是通过G蛋白在细胞中传递编码在激素和神经递质中的信息的,而β-arrestins被认为是阻断这个过程的。

1
用β-arrestin2的生物传感器来研究

在第一篇欧洲学者的文章利用一系列的荧光共振能量转移(FRET)为基础的β-arrestin2的生物传感器,研究了β-arrestin和G蛋白偶联受体之间的相互作用以及β-arrestin在人活细胞中构象的实时变化。他们观察到,在受体与β-arrestin2之间快速作用后在β-arrestin2中受体特殊区域产生构象变化。激动剂清除后,这些变化持续的时间比受体直接作用要长。该研究的数据表明,在G蛋白偶联受体和β-arrestins之间是一个快速的,受体类型特异的,两步结合和激活的过程。进一步的研究表明,β-arrestins从受体解离后保持活跃,这允许它们能够留在细胞表面保持信号独立。这样G蛋白偶联受体触发β-arrestins快速的、受体特异的激活/失活的循环,这允许它们有传递信号的活性。

2
模拟β-arrestin2中的构象变化

第二篇美国学者的文章使用分子内荧光砷剂发夹(FlAsH)生物发光共振能量转移(BRET)受体来模拟β-arrestin2中的构象变化。研究人员发现G蛋白偶联受体有独特的arrestin的构象标记,反映了受体和arrestin复合物的稳定性以及β-arrestin2在下游信号事件中活化或抑制的作用。这些标记的预测值包括结构不同的配体激活相同的G蛋白偶联受体,所以配体的本质属性反应β-arrestin2的构象变化。研究结果表明关于配体-受体复合物构象的信息是编码在β-arrestin2构象的平均群体值中,并显示了不同的G蛋白偶联受体可作为不同用途的共同效应因子。这个发现也许能运用在描述和发展G蛋白偶联受体的功能性选择上和鉴定调控arrestin构象和功能的因子。

3
治疗前景

由于G蛋白系统的多样性,G蛋白偶联受体和G蛋白信号转导是治疗药物的重要靶点,有时也会产生不必要的副作用。通过开发分子促进β-arrestins的信号而不是G蛋白的,也许能够克服这些问题。正是这项新的研究,有可能在强止痛药长期治疗中有特别好的进展。

事实上,在分子水平上特别激活β-arrestins的新药物能减少身体对药物耐受的发展,因此任何副作用的患者,可以有一个更有效的长期治疗。

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  • The conformational signature of β-arrestin2 predicts its trafficking and signalling functions

    Arrestins are cytosolic proteins that regulate G-protein-coupled receptor (GPCR) desensitization, internalization, trafficking and signalling. Arrestin recruitment uncouples GPCRs from heterotrimeric G proteins, and targets the proteins for internalization via clathrin-coated pits. Arrestins also function as ligand-regulated scaffolds that recruit multiple non-G-protein effectors into GPCR-based ‘signalsomes’. Although the dominant function(s) of arrestins vary between receptors, the mechanism whereby different GPCRs specify these divergent functions is unclear. Using a panel of intramolecular fluorescein arsenical hairpin (FlAsH) bioluminescence resonance energy transfer (BRET) reporters7 to monitor conformational changes in β-arrestin2, here we show that GPCRs impose distinctive arrestin ‘conformational signatures’ that reflect the stability of the receptor–arrestin complex and role of β-arrestin2 in activating or dampening downstream signalling events. The predictive value of these signatures extends to structurally distinct ligands activating the same GPCR, such that the innate properties of the ligand are reflected as changes in β-arrestin2 conformation. Our findings demonstrate that information about ligand–receptor conformation is encoded within the population average β-arrestin2 conformation, and provide insight into how different GPCRs can use a common effector for different purposes. This approach may have application in the characterization and development of functionally selective GPCR ligands and in identifying factors that dictate arrestin conformation and function.

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  • β-Arrestin biosensors reveal a rapid, receptor-dependent activation/deactivation cycle

    (β-)Arrestins are important regulators of G-protein-coupled receptors (GPCRs). They bind to active, phosphorylated GPCRs and thereby shut off ‘classical’ signalling to G proteins, trigger internalization of GPCRs via interaction with the clathrin machinery and mediate signalling via ‘non-classical’ pathways. In addition to two visual arrestins that bind to rod and cone photoreceptors (termed arrestin1 and arrestin4), there are only two (non-visual) β-arrestin proteins (β-arrestin1 and β-arrestin2, also termed arrestin2 and arrestin3), which regulate hundreds of different (non-visual) GPCRs. Binding of these proteins to GPCRs usually requires the active form of the receptors plus their phosphorylation by G-protein-coupled receptor kinases (GRKs). The binding of receptors or their carboxy terminus as well as certain truncations induce active conformations of (β-)arrestins that have recently been solved by X-ray crystallography8, 9, 10. Here we investigate both the interaction of β-arrestin with GPCRs, and the β-arrestin conformational changes in real time and in living human cells, using a series of fluorescence resonance energy transfer (FRET)-based β-arrestin2 biosensors. We observe receptor-specific patterns of conformational changes in β-arrestin2 that occur rapidly after the receptor–β-arrestin2 interaction. After agonist removal, these changes persist for longer than the direct receptor interaction. Our data indicate a rapid, receptor-type-specific, two-step binding and activation process between GPCRs and β-arrestins. They further indicate that β-arrestins remain active after dissociation from receptors, allowing them to remain at the cell surface and presumably signal independently. Thus, GPCRs trigger a rapid, receptor-specific activation/deactivation cycle of β-arrestins, which permits their active signalling.

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