Neural cell adhesion molecule function is regulated by metalloproteinase-mediated ectodomain release
Neural cell adhesion molecule function is regulated by metalloproteinase-mediated ectodomain release
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DOI：
10.1002/jnr.20530
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发表时间：
2005-06-15
影响因子：
4.2
通讯作者：
Berezin, V
中科院分区：
文献类型：
--
作者：
Hübschmann, MV;Skladchikova, G;Berezin, V
神经细胞黏附分子(NCAM)参与神经系统的发育、与学习和记忆相关的大脑可塑性以及神经元再生。NCAM通过影响细胞黏附、细胞迁移和轴突生长来调节这些过程。NCAM在NCAM结合时激活细胞内信号，这是NCAM刺激神经突起生长的先决条件。NCAM的合成有三种主要的膜结合异构体：NCAM-120、NCAM-140和NCAM-180。在血液和脑脊液中也发现了NCAM的可溶性形式，尽管这些形式的功能意义尚不清楚。在这份报告中，我们证明了NCAM可以从原代培养的海马神经元中释放出来。应用三磷酸腺苷可促进细胞的释放，而金属蛋白酶抑制剂BB-3103则抑制释放。三磷酸腺苷还诱导NCAM3种主要的NCAM亚型从转染成纤维细胞的L细胞中释放出来。在该模型体系中，NCAM的胞外ATP结合部位不是ATP诱导的NCAM释放所必需的。此外，丝氨酸、半胱氨酸和天冬氨酸蛋白酶的抑制不能阻止三磷酸腺苷诱导的L细胞中NCAM的下调，这表明NCAM直接被金属蛋白酶切割。在金属蛋白酶抑制剂GM 6001存在的情况下，培养的海马神经元聚集增加，这与这些细胞中发生的金属蛋白酶依赖的NCAM脱落一致。此外，应用GM6001可显著减少NCAM依赖的轴突生长。综上所述，这些结果表明，膜结合的NCAM可以被金属蛋白酶进行细胞外切割，金属蛋白酶依赖的NCAM的脱落调节NCAM介导的神经突起生长。(C)2005年Wiley-Liss，Inc.
The neural cell adhesion molecule (NCAM) is involved in development of the nervous system, in brain plasticity associated with learning and memory, and in neuronal regeneration. NCAM regulates these processes by influencing cell adhesion, cell migration, and neurite outgrowth. NCAM activates intracellular signaling upon homophilic NCAM binding, and this is a prerequisite for NCAM-stimulated neurite outgrowth. NCAM is synthesized in three main membrane-bound isoforms, NCAM-120, NCAM-140, and NCAM-180. Soluble forms of NCAM in blood and cerebrospinal fluid have also been found, although the functional significance of these forms remains unclear. In this report, we demonstrate that NCAM can be released from primary hippocampal neurons in culture. The release was enhanced by application of ATP and inhibited by the metalloproteinase inhibitor BB-3103. ATP also induced metalloproteinase-dependent release of all three major NCAM isoforms from NCAM-transfected fibroblastoid L-cells. In this model system, the extracellular ATP-binding site of NCAM was shown not to be necessary for ATP-induced NCAM release. Furthermore, inhibition of serine, cysteine, and aspartic proteinases could not prevent ATP-induced down-regulation of NCAM in L-cells, suggesting that NCAM is cleaved directly by a metalloproteinase. Aggregation of hippocampal neurons in culture was increased in the presence of the metalloproteinase inhibitor GM 6001, consistent with a metalloproteinase-dependent shedding of NCAM occurring in these cells. Moreover, NCAM-dependent neurite outgrowth was significantly reduced by application of GM 6001. Taken together, these results suggest that membrane-bound NCAM can be cleaved extracellularly by a metalloproteinase and that metalloproteinase-dependent shedding of NCAM regulates NCAM-mediated neurite outgrowth. (c) 2005 Wiley-Liss, Inc.