Activity-dependent ubiquitination of GluA1 mediates a distinct AMPA receptor endocytosis and sorting pathway.
Activity-dependent ubiquitination of GluA1 mediates a distinct AMPA receptor endocytosis and sorting pathway.
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DOI：
10.1523/jneurosci.3686-10.2010
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发表时间：
2010-12-08
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影响因子：
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通讯作者：
Patrick GN
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作者：
Schwarz LA;Hall BJ;Patrick GN
AMPA受体（AMPAR）准确地运输到突触和从突触运输是大脑中学习和记忆的关键组成部分，而AMPAR运输功能障碍被假设为阿尔茨海默病的潜在机制。先前的工作已经表明，整合膜蛋白的泛素化是一种常见的翻译后修饰，用于介导真核细胞中表面蛋白的内吞和内吞分选。在这里，我们报告说，哺乳动物的AMPAR成为泛素化的响应，他们的激活。使用的突变体的GluA 1是不能被泛素化的赖氨酸在其羧基末端，我们证明，泛素化是必需的表面AMPAR的内化和他们的运输到溶酶体中的响应AMPAR激动剂AMPA，但不是响应NMDA受体（NMDAR）激动剂NMDA的AMPAR的内化。通过过表达或RNAi介导的敲低，我们确定了一个特定的E3连接酶，Nedd 4 -1，是这个过程所必需的。最后，我们发现，Nedd 4 -1的GluA 1的泛素化变得更加普遍的神经元成熟。总之，这些数据表明，泛素化的GluA 1含有AMPAR的Nedd 4 -1介导的内吞作用和运输到溶酶体。此外，这些结果提供了洞察海马神经元如何调节AMPAR的运输和降解，响应不同的神经元信号线索的高特异性，并表明这种途径的变化可能会发生神经元成熟。
The accurate trafficking of AMPA receptors (AMPARs) to and from the synapse is a critical component of learning and memory in the brain, while dysfunction of AMPAR trafficking is hypothesized to be an underlying mechanism of Alzheimer’s disease. Previous work has shown that ubiquitination of integral membrane proteins is a common post-translational modification used to mediate endocytosis and endocytic sorting of surface proteins in eukaryotic cells. Here we report that mammalian AMPARs become ubiquitinated in response to their activation. Using a mutant of GluA1 that is unable to be ubiquitinated at lysines on its carboxy-terminus, we demonstrate that ubiquitination is required for internalization of surface AMPARs and their trafficking to the lysosome in response to the AMPAR agonist AMPA, but not for internalization of AMPARs in response to the NMDA receptor (NMDAR) agonist NMDA. Through over-expression or RNAi-mediated knockdown, we identify that a specific E3 ligase, Nedd4-1, is necessary for this process. Finally, we show that ubiquitination of GluA1 by Nedd4-1 becomes more prevalent as neurons mature. Together, these data show that ubiquitination of GluA1-containing AMPARs by Nedd4-1 mediates their endocytosis and trafficking to the lysosome. Furthermore, these results provide insight into how hippocampal neurons regulate AMPAR trafficking and degradation with high specificity in response to differing neuronal signaling cues, and suggest that changes to this pathway may occur as neurons mature.