Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1
Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1
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DOI：
10.1038/nn1680
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发表时间：
2006-05-01
影响因子：
25
通讯作者：
Ehlers, MD
中科院分区：
文献类型：
--
作者：
Pérez-Otaño, I;Luján, R;Ehlers, MD
谷氨酸突触成熟的一个关键步骤是发育表达的n -甲基- d -天冬氨酸受体（NMDARs）被成熟的形式所取代，这些受体在亚基组成、电生理特性和引发突触可塑性的倾向方面存在差异。然而，突触NMDARs的移除和替换机制尚不清楚。本研究表明，在培养的大鼠海马神经元中，含有发育调节的NR3A亚基的NMDARs可以从树突质膜上快速内吞。这种内吞去除是由PACSIN1/syndapin1调控的，PACSIN1/syndapin1通过其NPF基序直接和选择性地结合NR3A的羧基末端结构域，并组装包括动力蛋白和网格蛋白在内的蛋白质复合物。PACSIN1对NR3A的内吞作用是活性依赖的，PACSIN1功能的破坏会导致NR3A在突触位点的积累。我们的研究结果揭示了一种新的活动依赖机制，涉及发育过程中突触中NMDAR表达的调节，并鉴定了一种脑特异性内吞接头，该接头赋予NMDAR内吞的时空和亚基特异性。
A key step in glutamatergic synapse maturation is the replacement of developmentally expressed N-methyl-D-aspartate receptors (NMDARs) with mature forms that differ in subunit composition, electrophysiological properties and propensity to elicit synaptic plasticity. However, the mechanisms underlying the removal and replacement of synaptic NMDARs are poorly understood. Here we demonstrate that NMDARs containing the developmentally regulated NR3A subunit undergo rapid endocytosis from the dendritic plasma membrane in cultured rat hippocampal neurons. This endocytic removal is regulated by PACSIN1/syndapin1, which directly and selectively binds the carboxy-terminal domain of NR3A through its NPF motifs and assembles a complex of proteins including dynamin and clathrin. Endocytosis of NR3A by PACSIN1 is activity dependent, and disruption of PACSIN1 function causes NR3A accumulation at synaptic sites. Our results reveal a new activity-dependent mechanism involved in the regulation of NMDAR expression at synapses during development, and identify a brain-specific endocytic adaptor that confers spatiotemporal and subunit specificity to NMDAR endocytosis.