Agnati L F, Leo G, Genedani S, Andreoli N, Marcellino D, Woods A, Piron L, Guidolin D, Fuxe K
Section of Physiology, Department of Biomedical Sciences, University of Modena, 41100 Modena, Italy.
Brain Res Rev. 2008 Aug;58(2):459-74. doi: 10.1016/j.brainresrev.2007.10.003. Epub 2007 Oct 22.
Structural plasticity of G-protein coupled receptors (GPCRs) is of basic importance for their interactions with ligands, in particular with other proteins such as receptors or receptor-modifying proteins that can lead to different functions for the same GPCR. In the present paper, structural plasticity of GPCRs has been investigated discussing allosteric modulatory actions of Homocysteine (Hcy) on D2 receptors together with data obtained by computer-assisted analysis of the presence of disordered domains in GPCRs. Previous evidence for a modulatory action of Hcy on D2 receptors has been further extended by means of experiments on the effects of Hcy local intrastriatal injection on rotational behaviour. Altogether the present data allow considering under a new angle the well known proposal of A2A antagonists as new therapeutic agents in Parkinson's disease (PD). Furthermore, they point out to not only the importance of drugs capable of reducing Hcy brain levels, but also to the potential therapeutic impact of drugs capable of regionally blocking (for PD) or enhancing (for some schizophrenic syndromes) Hcy allosteric action on D2 receptors. As far as the investigations on GPCR plastic domains, extracellular, intracellular and transmembrane domains of 14 GPCRs have been considered and propensity of each of these domains for a structured or unstructured conformation has been evaluated by means of ad hoc computer programs. It has been shown that the N- and C-terminals as well as intracellular loop 3 have a high propensity towards an unstructured conformation, hence they are potentially very plastic domains, which can undergo easily to interactions with other ligands, particularly with other protein domains. This aspect is obviously of the greatest importance not only for the function of single GPCRs, but also for their interactions either with other receptors (receptor-receptor interactions) or, more generally, for formation of clusters of membrane associated proteins, hence of "protein mosaics", where the GPCRs could represent the input unit of the supra-molecular device.
G蛋白偶联受体（GPCRs）的结构可塑性对于其与配体的相互作用至关重要，特别是与其他蛋白质（如受体或受体修饰蛋白）的相互作用，这可能导致同一GPCR产生不同的功能。在本文中，研究了GPCRs的结构可塑性，讨论了同型半胱氨酸（Hcy）对D2受体的变构调节作用，以及通过计算机辅助分析GPCRs中无序结构域的存在所获得的数据。通过Hcy纹状体内局部注射对旋转行为影响的实验，进一步扩展了Hcy对D2受体调节作用的先前证据。总体而言，目前的数据允许从一个新的角度考虑A2A拮抗剂作为帕金森病（PD）新治疗药物的著名提议。此外，它们不仅指出了能够降低脑中Hcy水平的药物的重要性，还指出了能够局部阻断（针对PD）或增强（针对某些精神分裂症综合征）Hcy对D2受体变构作用的药物的潜在治疗影响。就GPCR可塑性结构域的研究而言，已考虑了14种GPCR的细胞外、细胞内和跨膜结构域，并通过专门的计算机程序评估了这些结构域中每一个形成结构化或非结构化构象的倾向。结果表明，N端和C端以及细胞内环3具有很高的形成非结构化构象的倾向，因此它们可能是非常可塑性的结构域，能够很容易地与其他配体相互作用，特别是与其他蛋白质结构域相互作用。这一方面显然不仅对于单个GPCR的功能非常重要，而且对于它们与其他受体的相互作用（受体-受体相互作用），或者更一般地说，对于膜相关蛋白簇的形成，即“蛋白质镶嵌体”的形成非常重要，其中GPCR可能代表超分子装置的输入单元。
