GSK-3ß regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIa
GSK-3ß regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIa
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GSK-3 通过 IIa 型磷脂酰肌醇 4 激酶的磷酸化调节 NMDA 受体的突触表达
DOI：
10.1101/841676
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Amici M
中科院分区：
文献类型：
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作者：
Amici M
GSK-3β的失调与多种严重的脑部疾病密切相关，如阿尔茨海默病、双相情感障碍和精神分裂症。为了了解GSK-3β在这些情况下如何变得失调，了解其在中枢神经系统中的生理功能非常重要。在这种情况下，GSK-3β在诱导NMDA受体依赖性长期抑制（LTD）中发挥作用，并且已经在这种形式的突触可塑性中鉴定了GSK-3β的几种底物，包括KLC-2，PSD-95和tau。突触处NMDA受体的稳定性也已被证明涉及GSK-3β，但所涉及的底物目前尚不清楚。最近的工作已经确定磷脂酰肌醇4激酶IIα（PI 4KII α）作为神经元GSK-3β底物，可以潜在地调节AMPA受体的表面表达。在本研究中，我们研究了在器官型大鼠海马脑片中PI 4 KII α的突触作用。我们发现，PI 4KII α的敲低对突触AMPA受体介导的突触传递没有影响，但大大减少了NMDA受体介导的突触传递。此外，选择性GSK-3抑制剂CT 99021降低NMDA受体介导的电流振幅的能力在shRNA-PI 4KII α转染的神经元中被阻断。敲低PI 4KII α的效果完全被shRNA抗性野生型构建体所拯救，但不能被GSK-3β磷酸化的突变体构建体所拯救。这些数据表明GSK-3β磷酸化PI 4KII α以稳定突触处的NMDA受体。
Deregulation of GSK‐3β is strongly implicated in a variety of serious brain conditions, such as Alzheimer disease, bipolar disorder and schizophrenia. To understand how GSK‐3β becomes dysregulated in these conditions, it is important to understand its physiological functions in the central nervous system. In this context, GSK‐3β plays a role in the induction of NMDA receptor‐dependent long‐term depression (LTD) and several substrates for GSK‐3β have been identified in this form of synaptic plasticity, including KLC‐2, PSD‐95 and tau. Stabilization of NMDA receptors at synapses has also been shown to involve GSK‐3β, but the substrates involved are currently unknown. Recent work has identified phosphatidylinositol 4 kinase type IIα (PI4KIIα) as a neuronal GSK‐3β substrate that can potentially regulate the surface expression of AMPA receptors. In the present study, we investigated the synaptic role of PI4KIIα in organotypic rat hippocampal slices. We found that knockdown of PI4KIIα has no effect on synaptic AMPA receptor‐mediated synaptic transmission but substantially reduces NMDA receptor‐mediated synaptic transmission. Furthermore, the ability of the selective GSK‐3 inhibitor, CT99021, to reduce the amplitude of NMDA receptor‐mediated currents was occluded in shRNA‐PI4KIIα transfected neurons. The effects of knocking down PI4KIIα were fully rescued by a shRNA‐resistant wild‐type construct, but not by a mutant construct that cannot be phosphorylated by GSK‐3β. These data suggest that GSK‐3β phosphorylates PI4KIIα to stabilize NMDA receptors at the synapse.