Hippocampal synaptic modulation by the phosphotyrosine adapter protein ShcC/N-Shc via interaction with the NMDA receptor
Hippocampal synaptic modulation by the phosphotyrosine adapter protein ShcC/N-Shc via interaction with the NMDA receptor
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DOI：
10.1523/jneurosci.3030-04.2005
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发表时间：
2005-02-16
影响因子：
5.3
通讯作者：
Mori, N
中科院分区：
文献类型：
--
作者：
Miyamoto, Y;Chen, L;Mori, N
N-Shc（神经Shc）（也称为ShcC）是一种具有两个磷酸酪氨酸结合基序[PTB（磷酸酪氨酸结合）和SH 2（Src同源2）结构域]的衔接蛋白，主要在CNS的成熟神经元中表达，并将神经营养因子信号从TrkB受体传递至Ras/促分裂原活化蛋白激酶（MAPK）途径，导致细胞生长、分化或存活。在这里，我们证明了一个新的作用，ShcC，在海马NMDA受体功能的调制，使用ShcC基因缺陷小鼠。在Morris水迷宫、情境恐惧条件反射和新物体识别任务等行为分析中，ShcC突变小鼠表现出上级的海马区依赖性空间和非空间学习和记忆能力。与这一发现相一致，电生理学分析显示，海马长时程增强ShcC突变小鼠，突触前功能没有改变，其在突变小鼠的表达的NMDA受体拮抗剂的效果显着减弱。NMDA受体亚基NR 2A和NR 2B的酪氨酸磷酸化也增加，表明ShcC突变小鼠在海马中具有增强的NMDA受体功能。这些结果表明，ShcC不仅介导TrkB-Ras/MAPK信号转导，而且还通过与受体亚基上的磷酸酪氨酸残基的相互作用参与海马中NMDA受体功能的调节，并作为海马突触可塑性的调节剂，其基础是学习和记忆。
N-Shc (neural Shc) (also ShcC), an adapter protein possessing two phosphotyrosine binding motifs [PTB (phosphotyrosine binding) and SH2 (Src homology 2) domains], is predominantly expressed in mature neurons of the CNS and transmits neurotrophin signals from the TrkB receptor to the Ras/mitogen-activated protein kinase (MAPK) pathway, leading to cellular growth, differentiation, or survival. Here, we demonstrate a novel role of ShcC, the modulation of NMDA receptor function in the hippocampus, using ShcC gene-deficient mice. In behavioral analyses such as the Morris water maze, contextual fear conditioning, and novel object recognition tasks, ShcC mutant mice exhibited superior ability in hippocampus-dependent spatial and nonspatial learning and memory. Consistent with this finding, electrophysiological analyses revealed that hippocampal long-term potentiation in ShcC mutant mice was significantly enhanced, with no alteration of presynaptic function, and the effect of an NMDA receptor antagonist on its expression in the mutant mice was notably attenuated. The tyrosine phosphorylation of NMDA receptor subunits NR2A and NR2B was also increased, suggesting that ShcC mutant mice have enhanced NMDA receptor function in the hippocampus. These results indicate that ShcC not only mediates TrkB-Ras/MAPK signaling but also is involved in the regulation of NMDA receptor function in the hippocampus via interaction with phosphotyrosine residues on the receptor subunits and serves as a modulator of hippocampal synaptic plasticity underlying learning and memory.