Yokomaku D, Jourdi H, Kakita A, Nagano T, Takahashi H, Takei N, Nawa H
Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Asahimachi-dori 1-757, Niigata 951-8585, Japan.
Neuroscience. 2005;136(4):1037-47. doi: 10.1016/j.neuroscience.2005.08.014. Epub 2005 Oct 14.
Scaffolding proteins containing postsynaptic density-95/discs large/zone occludens-1 (PDZ) domains interact with synaptic receptors and cytoskeletal components and are therefore implicated in synaptic development and plasticity. Little is known, however, about what regulates the expression of PDZ proteins and how the levels of these proteins influence synaptic development. Here, we show that ligands for epidermal growth factor receptors (ErbB1) decrease a particular set of PDZ proteins and negatively influence synaptic formation or maturation. In short-term neocortical cultures, concentrations of epidermal growth factor and amphiregulin (2-9 pM) decreased the expression of glutamate receptor interacting protein 1 (GRIP1) and synapse-associated protein 97 kDa (SAP97) without affecting postsynaptic density-95 (PSD-95) levels and glial proliferation. In long-term cultures, epidermal growth factor treatment resulted in a decrease in the frequency of pan-PDZ-immunoreactive aggregates on dendritic processes. A similar activity on the same PDZ proteins was observed in the developing neocortex following epidermal growth factor administration to rat neonates. Immunoblotting revealed that administered epidermal growth factor from the periphery activated brain ErbB1 receptors and decreased GRIP1 and SAP97 protein levels in the neocortex. Laser-confocal imaging indicated that epidermal growth factor administration suppressed the formation of pan-PDZ-immunoreactive puncta and dispersed those structures in vivo as well. These findings revealed a novel negative activity of ErbB1 receptor ligands that attenuates the expression of the PDZ proteins and inhibits postsynaptic maturation in developing neocortex.
含有突触后致密蛋白95/大盘状蛋白/紧密连接蛋白1（PDZ）结构域的支架蛋白与突触受体和细胞骨架成分相互作用，因此与突触发育和可塑性有关。然而，关于什么调节PDZ蛋白的表达以及这些蛋白的水平如何影响突触发育，我们知之甚少。在这里，我们表明表皮生长因子受体（ErbB1）的配体减少了一组特定的PDZ蛋白，并对突触形成或成熟产生负面影响。在短期新皮质培养物中，表皮生长因子和双调蛋白（2 - 9 pM）的浓度降低了谷氨酸受体相互作用蛋白1（GRIP1）和突触相关蛋白97 kDa（SAP97）的表达，而不影响突触后致密蛋白95（PSD - 95）水平和胶质细胞增殖。在长期培养物中，表皮生长因子处理导致树突过程中泛PDZ免疫反应性聚集体的频率降低。在给新生大鼠注射表皮生长因子后，在发育中的新皮质中观察到对相同PDZ蛋白的类似作用。免疫印迹显示，从外周给予的表皮生长因子激活了脑内的ErbB1受体，并降低了新皮质中GRIP1和SAP97蛋白的水平。激光共聚焦成像表明，给予表皮生长因子也抑制了体内泛PDZ免疫反应性斑点的形成并使这些结构分散。这些发现揭示了ErbB1受体配体的一种新的负性作用，即减弱PDZ蛋白的表达并抑制发育中新皮质的突触后成熟。
