Coba Marcelo P, Pocklington Andrew J, Collins Mark O, Kopanitsa Maksym V, Uren Rachel T, Swamy Sajani, Croning Mike D R, Choudhary Jyoti S, Grant Seth G N
Genes to Cognition, Wellcome Trust Sanger Institute, Cambridgeshire, UK.
Sci Signal. 2009 Apr 28;2(68):ra19. doi: 10.1126/scisignal.2000102.
The mammalian postsynaptic density (PSD) comprises a complex collection of approximately 1100 proteins. Despite extensive knowledge of individual proteins, the overall organization of the PSD is poorly understood. Here, we define maps of molecular circuitry within the PSD based on phosphorylation of postsynaptic proteins. Activation of a single neurotransmitter receptor, the N-methyl-D-aspartate receptor (NMDAR), changed the phosphorylation status of 127 proteins. Stimulation of ionotropic and metabotropic glutamate receptors and dopamine receptors activated overlapping networks with distinct combinatorial phosphorylation signatures. Using peptide array technology, we identified specific phosphorylation motifs and switching mechanisms responsible for the integration of neurotransmitter receptor pathways and their coordination of multiple substrates in these networks. These combinatorial networks confer high information-processing capacity and functional diversity on synapses, and their elucidation may provide new insights into disease mechanisms and new opportunities for drug discovery.
哺乳动物的突触后致密区（PSD）由大约1100种蛋白质组成的复杂集合体构成。尽管对单个蛋白质已有广泛了解，但PSD的整体组织却知之甚少。在此，我们基于突触后蛋白的磷酸化作用定义了PSD内的分子电路图。单一神经递质受体——N-甲基-D-天冬氨酸受体（NMDAR）的激活改变了127种蛋白质的磷酸化状态。离子型和代谢型谷氨酸受体以及多巴胺受体的刺激激活了具有不同组合磷酸化特征的重叠网络。利用肽阵列技术，我们确定了负责神经递质受体途径整合及其在这些网络中对多个底物进行协调的特定磷酸化基序和转换机制。这些组合网络赋予突触高信息处理能力和功能多样性，对它们的阐释可能为疾病机制提供新见解，并为药物发现带来新机遇。
