Department of Medicine II, University Hospital and University of Freiburg, 79104 Freiburg, Germany.
J Biol Chem. 2013 Jul 26;288(30):21909-23. doi: 10.1074/jbc.M112.444364. Epub 2013 Jun 11.
The lipoprotein receptor LRP1 is essential in neurons of the central nervous system, as was revealed by the analysis of conditional Lrp1-deficient mouse models. The molecular basis of its neuronal functions, however, is still incompletely understood. Here we show by immunocytochemistry, electron microscopy, and postsynaptic density preparation that LRP1 is located postsynaptically. Basal and NMDA-induced phosphorylation of the transcription factor cAMP-response element-binding protein (CREB) as well as NMDA target gene transcription are reduced in LRP1-deficient neurons. In control neurons, NMDA promotes γ-secretase-dependent release of the LRP1 intracellular domain (LRP1-ICD). However, pull-down and chromatin immunoprecipitation (ChIP) assays showed no direct interaction between the LRP1-ICD and either CREB or target gene promoters. On the other hand, NMDA-induced degradation of the postsynaptic scaffold protein PSD-95 was impaired in the absence of LRP1, whereas its ubiquitination was increased, indicating that LRP1 influences the composition of postsynaptic protein complexes. Accordingly, NMDA-induced internalization of the AMPA receptor subunit GluA1 was impaired in LRP1-deficient neurons. These results show a role of LRP1 in the regulation and turnover of synaptic proteins, which may contribute to the reduced dendritic branching and to the neurological phenotype observed in the absence of LRP1.
载脂蛋白受体 LRP1 在中枢神经系统的神经元中是必不可少的，这一点可以通过对条件性 Lrp1 缺陷型小鼠模型的分析来揭示。然而，其神经元功能的分子基础仍不完全清楚。在这里，我们通过免疫细胞化学、电子显微镜和突触后密度制备显示 LRP1 位于突触后。LRP1 缺失神经元中，基础和 NMDA 诱导的转录因子 cAMP 反应元件结合蛋白（CREB）磷酸化以及 NMDA 靶基因转录减少。在对照神经元中，NMDA 促进 γ-分泌酶依赖性释放 LRP1 细胞内结构域（LRP1-ICD）。然而，下拉和染色质免疫沉淀（ChIP）实验表明 LRP1-ICD 与 CREB 或靶基因启动子之间没有直接相互作用。另一方面，在缺乏 LRP1 的情况下，NMDA 诱导的突触后支架蛋白 PSD-95 降解受损，而其泛素化增加，表明 LRP1 影响突触后蛋白复合物的组成。因此，LRP1 缺失神经元中 NMDA 诱导的 AMPA 受体亚基 GluA1 内化受损。这些结果表明 LRP1 在调节和翻转突触蛋白中的作用，这可能有助于减少树突分支，并导致 LRP1 缺失时观察到的神经表型。
