Reelin modulates NMDA receptor activity in cortical neurons
Reelin modulates NMDA receptor activity in cortical neurons
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DOI：
10.1523/jneurosci.1951-05.2005
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发表时间：
2005-09-07
影响因子：
5.3
通讯作者：
Herz, J
中科院分区：
文献类型：
--
作者：
Chen, Y;Beffert, U;Herz, J
Reelin是一种调节胚胎发育过程中神经元迁移的大蛋白，它激活了一条保守的信号通路，该通路需要其受体，极低密度脂蛋白受体和载脂蛋白E受体2，细胞质接头蛋白Disabled-1 （Dab1）和Src家族激酶（SFK）。Reelin还显著增强了成人海马的长期增强，表明这种发育信号通路可以生理调节学习和行为。在这里，我们发现Reelin可以通过一种需要SFKs和Dab1的机制调节nmda型谷氨酸受体的活性。在原代野生型皮质神经元中，Reelin介导酪氨酸磷酸化并增强钙通过NMDA受体的内流，但在Dab1敲除的神经元中或在Reelin与其受体结合被受体拮抗剂阻断的细胞中则没有。抑制SFK可消除reelin诱导和谷氨酸依赖的钙内流增强。我们还表明，reelin诱导的Ca2+通过NMDA受体进入的增加增加了转录因子camp反应元件结合蛋白的磷酸化和核易位。因此，Reelin可能通过调节NMDA受体的功能来生理调节学习和记忆。
Reelin, a large protein that regulates neuronal migration during embryonic development, activates a conserved signaling pathway that requires its receptors, very low-density lipoprotein receptor and apolipoprotein E receptor 2, the cytoplasmic adaptor protein Disabled-1 (Dab1), and Src family kinases (SFK). Reelin also markedly enhances long-term potentiation in the adult hippocampus, suggesting that this developmental signaling pathway can physiologically modulate learning and behavior. Here, we show that Reelin can regulate NMDA-type glutamate receptor activity through a mechanism that requires SFKs and Dab1. Reelin mediates tyrosine phosphorylation of and potentiates calcium influx through NMDA receptors in primary wild-type cortical neurons but not in Dab1 knock-out neurons or in cells in which Reelin binding to its receptors is blocked by a receptor antagonist. Inhibition of SFK abolishes Reelin-induced and glutamate-dependent enhancement of calcium influx. We also show that Reelin-induced augmentation of Ca2+ entry through NMDA receptors increases phosphorylation and nuclear translocation of the transcription factor cAMP-response element binding protein. Thus, Reelin may physiologically modulate learning and memory by modulating NMDA receptor functions.