NMDA receptor-dependent synaptic translocation of insulin receptor substrate p53 via protein kinase C signaling
NMDA receptor-dependent synaptic translocation of insulin receptor substrate p53 via protein kinase C signaling
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DOI：
10.1523/jneurosci.3638-04.2005
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发表时间：
2005-03-09
影响因子：
5.3
通讯作者：
Sobue, K
中科院分区：
文献类型：
--
作者：
Hori, K;Yasuda, H;Sobue, K
依赖活动的突触后结构重塑是学习和记忆的基本过程。胰岛素受体底物P53(IRSP53)是细胞骨架动力学中的关键分子，富含突触后密度(PSD)，但其在突触功能中的意义尚不清楚。我们报道，在谷氨酸或NMDA刺激后，IRSP53以肌动蛋白细胞骨架依赖的方式在培养的海马神经元突触后迅速积聚。药理学研究表明，在NMDA刺激下，一种PKC抑制剂可特异性抑制IRSP53的突触移位，而佛波酯选择性激活PKC可显著诱导突触移位。逆转录酶-聚合酶链式反应和Western blotting结果表明，IRSP53-S是培养的海马神经元表达的主要亚型。IRSP53-S的突触靶向性是通过其N端的螺旋线圈结构域和其C端的PDZ(PsD-95/Discs Large/Zona occludens-1)结合序列介导的，并受其N端的PKC磷酸化调控。在电生理实验中，自发积累在突触后部位的IRSP53-S野生型和IRSP53-S突变体的过表达增强了突触后功能，其表现为微小的EPSC幅度增加。这些数据表明，IRSP53通过PKC信号参与了NMDA受体相关的突触可塑性。
The activity-dependent remodeling of postsynaptic structure is a fundamental process underlying learning and memory. Insulin receptor substrate p53 (IRSp53), a key player in cytoskeletal dynamics, is enriched in the postsynaptic density (PSD) fraction, but its significance in synaptic functions remains unclear. We report here that IRSp53 is accumulated rapidly at the postsynaptic sites of cultured hippocampal neurons after glutamate or NMDA stimulation in an actin cytoskeleton-dependent manner. Pharmacological profiles showed that a PKC inhibitor, but not other kinase inhibitors, specifically suppressed the synaptic translocation of IRSp53 in response to NMDA, and the selective activation of PKC with phorbol ester markedly induced the synaptic translocation. Reverse transcriptase-PCR and Western blotting showed that IRSp53-S is the major isoform expressed in cultured hippocampal neurons. The synaptic targeting of IRSp53-S was found to be mediated through N-terminal coiled-coil domain and the PDZ(PSD-95/Discs large/zona occludens-1)-binding sequence at its C-terminal end and regulated by the PKC phosphorylation of its N terminus. In electrophysiological experiments, overexpression of IRSp53-S wild type and IRSp53-S mutant that is spontaneously accumulated at the postsynaptic sites enhanced the postsynaptic function as detected by an increased miniature EPSC amplitude. These data suggest that IRSp53 is involved in NMDA receptor-linked synaptic plasticity via PKC signaling.