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铜蓝蛋白诱导 P19 神经元聚集涉及丝氨酸蛋白酶活性,并伴随着 Reelin 的裂解。

Ceruloplasmin-induced aggregation of P19 neurons involves a serine protease activity and is accompanied by reelin cleavage.

机构信息

Département de Chimie et de biochimie and Centre Biomed, Université du Québec à Montréal, Montreal, Quebec, Canada.

出版信息

Neuroscience. 2010 May 19;167(3):633-43. doi: 10.1016/j.neuroscience.2010.02.039. Epub 2010 Feb 24.

Abstract

The cytoarchitectural organization of the nervous system depends partly on extracellular serine proteases, including reelin. This 400K protein, which also exists as the N-terminally-derived 300K and 180K fragments, acts through binding to the lipoprotein receptors apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor (VLDLR). Ceruloplasmin (CP), a multifunctional protein found in the circulation and also expressed on glial cells, was shown to bind to, and induce aggregation of neurons newly differentiated from P19 embryonic stem cells. This indicated a potential developmental role of CP in neuronal organization, possibly in relation with reelin and other extracellular serine proteases. Therefore, we analysed the effect of cell-impermeant, large spectrum, serine protease inhibitors on CP-induced neuroaggregation and studied reelin expression. Soybean trypsin inhibitor and aprotinin (SBTI+Apro) inhibited CP neuroaggregative action. Undifferentiated and neurally-differentiating cultures secreted the 400K reelin. The 180K fragment was present during and after differentiation whereas the 300K species was barely detectable. However, CP stimulated generation of the 300K in the differentiated neuronal cultures, and SBTI+Apro abolished this CP effect. Time course profiles and function-blocking antibody indicated that neuroaggregation does not depend on the generation of the 300K fragment or on reelin action. CP neuroaggregative action thus involves a pericellular serine protease, different from reelin. On the other hand, the CP stimulation of reelin cleavage is in line with a possible role of CP in nervous system development. Since P19 cells express ApoER2 and VLDLR, they can help understanding relationships existing between CP, reelin and intervening protease(s).

摘要

神经系统的细胞结构组织部分依赖于细胞外丝氨酸蛋白酶,包括 reelin。这种 400kDa 的蛋白也以 N 端衍生的 300kDa 和 180kDa 片段形式存在,通过与脂蛋白受体载脂蛋白 E 受体 2(ApoER2)和极低密度脂蛋白受体(VLDLR)结合发挥作用。铜蓝蛋白(CP)是一种在循环中发现的多功能蛋白,也在神经胶质细胞上表达,已被证明能与新分化的 P19 胚胎干细胞神经元结合,并诱导其聚集。这表明 CP 在神经元组织中可能具有潜在的发育作用,可能与 reelin 和其他细胞外丝氨酸蛋白酶有关。因此,我们分析了细胞不透性、广谱丝氨酸蛋白酶抑制剂对 CP 诱导的神经聚集的影响,并研究了 reelin 的表达。大豆胰蛋白酶抑制剂和抑肽酶(SBTI+Apro)抑制 CP 的神经聚集作用。未分化和神经分化培养物分泌 400kDa 的 reelin。180kDa 片段在分化过程中和之后都存在,而 300kDa 片段几乎检测不到。然而,CP 刺激分化神经元培养物中 300kDa 片段的生成,SBTI+Apro 则消除了 CP 的这种作用。时程曲线和功能阻断抗体表明,神经聚集不依赖于 300kDa 片段的生成或 reelin 的作用。因此,CP 的神经聚集作用涉及一种细胞周丝氨酸蛋白酶,不同于 reelin。另一方面,CP 对 reelin 切割的刺激符合 CP 在神经系统发育中的可能作用。由于 P19 细胞表达 ApoER2 和 VLDLR,它们可以帮助理解 CP、reelin 和中间蛋白酶之间的关系。

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