Girdin Phosphorylation Is Crucial for Synaptic Plasticity and Memory: A Potential Role in the Interaction of BDNF/TrkB/Akt Signaling with NMDA Receptor
Girdin Phosphorylation Is Crucial for Synaptic Plasticity and Memory: A Potential Role in the Interaction of BDNF/TrkB/Akt Signaling with NMDA Receptor
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DOI：
10.1523/jneurosci.2228-14.2014
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发表时间：
2014-11-05
影响因子：
5.3
通讯作者：
Yamada, Kiyofumi
中科院分区：
文献类型：
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作者：
Nakai, Tsuyoshi;Nagai, Taku;Yamada, Kiyofumi
海马神经元的突触可塑性被认为代表了多种记忆。尽管越来越多的证据表明 BDNF/TrkB/Akt 信号在海马突触可塑性中发挥着至关重要的作用，但 Akt（一种丝氨酸/苏氨酸激酶）控制活动依赖性神经元可塑性的机制仍不清楚。 Girdin（也称为 APE、GIV 和 HkRP1）是一种肌动蛋白结合蛋白，参与肌动蛋白细胞骨架的重塑和细胞迁移，已被确定为 Akt 的底物。先前的研究表明，Girdin 缺陷 (Girdin(-/-)) 小鼠海马神经元迁移的缺陷与 Akt 对 Girdin S1416 (Girdin S1416) 的丝氨酸磷酸化无关。在本研究中，我们重点关注 Girdin S1416 磷酸化在与突触可塑性相关的 BDNF/TrkB/Akt 信号传导中的作用。我们发现海马中的 Girdin 在 S1416 位点以活性依赖性方式被磷酸化。 S1416被丙氨酸取代的磷酸化缺陷敲入小鼠（Girdin(SA/SA)小鼠）表现出脊柱收缩、海马长时程增强缺陷和记忆障碍。 Girdin(SA/SA) 小鼠的这些表型类似于 Girdin(+/-) 小鼠，后者的 Girdin 表达丢失了 50%。此外，Girdin 与 Src 激酶和 NMDA 受体 NR2B 亚基相互作用，导致 NR2B 亚基磷酸化和 NMDA 受体激活。我们的研究结果表明，Girdin 在海马体中具有两种不同的功能：不依赖于 Akt 的神经元迁移和通过与 Src 相互作用实现的 Akt 依赖性 NR2B 磷酸化，这与海马体中记忆形成的突触可塑性相关。
Synaptic plasticity in hippocampal neurons has been thought to represent a variety of memories. Although accumulating evidence indicates a crucial role of BDNF/TrkB/Akt signaling in the synaptic plasticity of the hippocampus, the mechanism by which Akt, a serine/threonine kinase, controls activity-dependent neuronal plasticity remains unclear. Girdin (also known as APE, GIV, and HkRP1), an actin-binding protein involved both in the remodeling of the actin cytoskeleton and in cell migration, has been identified as a substrate of Akt. Previous studies have demonstrated that deficit of neuronal migration in the hippocampus of Girdin-deficient (Girdin(-/-)) mice is independent on serine phosphorylation of Girdin at S1416 (Girdin S1416) by Akt. In the present study, we focused on the role of Girdin S1416 phosphorylation in BDNF/TrkB/Akt signaling associated with synaptic plasticity. We found that Girdin in the hippocampus was phosphorylated at S1416 in an activity-dependent manner. Phosphorylation-deficient knock-in mice (Girdin(SA/SA) mice), in which S1416 is replaced with alanine, exhibited shrinkage of spines, deficit of hippocampal long-term potentiation, and memory impairment. These phenotypes of Girdin(SA/SA) mice resembled those of Girdin(+/-) mice, which have 50% loss of Girdin expression. Furthermore, Girdin interacted with Src kinase and NR2B subunit of NMDA receptor, leading to phosphorylation of the NR2B subunit and NMDA receptor activation. Our findings suggest that Girdin has two different functions in the hippocampus: Akt-independent neuronal migration and Akt-dependent NR2B phosphorylation through the interaction with Src, which is associated with synaptic plasticity in the hippocampus underlying memory formation.