Zhang Yali, Guo Huifu, Kwan Helen, Wang Ji-Wu, Kosek Jon, Lu Bingwei
Department of Pathology, Stanford University School of Medicine, GRECC/VAPAHCS, Palo Alto, CA 94304, USA.
Neuron. 2007 Jan 18;53(2):201-15. doi: 10.1016/j.neuron.2006.12.016.
Targeting of synaptic molecules to their proper location is essential for synaptic differentiation and plasticity. PSD-95/Dlg proteins have been established as key components of the postsynapse. However, the molecular mechanisms regulating the synaptic targeting, assembly, and disassembly of PSD-95/Dlg are not well understood. Here we show that PAR-1 kinase, a conserved cell polarity regulator, is critically involved in controlling the postsynaptic localization of Dlg. PAR-1 is prominently localized at the Drosophila neuromuscular junction (NMJ). Loss of PAR-1 function leads to increased synapse formation and synaptic transmission, whereas overexpression of PAR-1 has the opposite effects. PAR-1 directly phosphorylates Dlg at a conserved site and negatively regulates its mobility and targeting to the postsynapse. The ability of a nonphosphorylatable Dlg to largely rescue PAR-1-induced synaptic defects supports the idea that Dlg is a major synaptic substrate of PAR-1. Control of Dlg synaptic targeting by PAR-1-mediated phosphorylation thus constitutes a critical event in synaptogenesis.
将突触分子靶向到其合适位置对于突触分化和可塑性至关重要。PSD-95/Dlg蛋白已被确立为突触后膜的关键组成部分。然而，调节PSD-95/Dlg突触靶向、组装和解聚的分子机制尚未完全清楚。在此我们表明，PAR-1激酶作为一种保守的细胞极性调节因子，在控制Dlg的突触后定位中起关键作用。PAR-1显著定位于果蝇神经肌肉接头（NMJ）。PAR-1功能缺失导致突触形成增加和突触传递增强，而PAR-1过表达则产生相反的效果。PAR-1直接在一个保守位点磷酸化Dlg，并负向调节其移动性和向突触后的靶向。一种不可磷酸化的Dlg在很大程度上挽救PAR-1诱导的突触缺陷的能力支持了Dlg是PAR-1的主要突触底物这一观点。因此，PAR-1介导的磷酸化对Dlg突触靶向的控制构成了突触发生中的一个关键事件。
