Activity-dependent ubiquitination of the AMPA receptor subunit GluA2.
Activity-dependent ubiquitination of the AMPA receptor subunit GluA2.
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DOI：
10.1523/jneurosci.5944-10.2011
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发表时间：
2011-02-23
期刊：
影响因子：
--
通讯作者：
Roche KW
中科院分区：
文献类型：
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作者：
Lussier MP;Nasu-Nishimura Y;Roche KW
AMPA受体（AMPAR）是突触后谷氨酸门控离子通道，介导哺乳动物大脑中的快速兴奋性神经传递。突触活动调节突触AMPAR的密度，从而影响突触功能、学习和记忆。因此，有强烈的兴趣，在定义的分子机制，调节AMPAR运输。兴奋性突触的突触后密度中的蛋白质表达受到泛素化的严格调节，泛素化是一种翻译后修饰，其动态调节蛋白质运输和降解以响应突触活性。令人惊讶的是，哺乳动物AMPAR的泛素化尚未报道。在这项研究中，我们证明，增加突触活动，通过与GABA（A）受体拮抗剂荷包牡丹碱治疗，快速和强大的诱导泛素化的GluA2 AMPAR亚基。类似地，用AMPAR激动剂治疗导致GluA2泛素化，这表明配体结合起关键作用。最后，我们发现，网格蛋白和动力蛋白依赖的内吞作用的AMPAR活性依赖的GluA2泛素化。我们的发现，GluA2经历活动依赖性泛素化扩展我们的理解，泛素化如何调节突触可塑性。
AMPA receptors (AMPARs) are postsynaptic glutamate-gated ion channels that mediate fast excitatory neurotransmission in the mammalian brain. Synaptic activity modulates the density of synaptic AMPARs, thereby affecting synaptic function, learning and memory. Consequently, there is intense interest in defining the molecular mechanisms regulating AMPAR trafficking. Protein expression in the postsynaptic density of excitatory synapses is tightly regulated by ubiquitination, a post-translational modification that dynamically regulates protein trafficking and degradation in response to synaptic activity. Surprisingly, the ubiquitination of mammalian AMPARs has not been reported. In this study, we demonstrate that increasing synaptic activity, via treatment with the GABA(A) receptor antagonist bicuculline, rapidly and robustly induces ubiquitination of the GluA2 AMPAR subunit. Similarly, treatment with AMPAR agonists results in GluA2 ubiquitination, which suggests that ligand-binding plays a critical role. Finally, we find that clathrin- and dynamin-dependent endocytosis of AMPARs is required for activity-dependent GluA2 ubiquitination. Our findings that GluA2 undergoes activity-dependent ubiquitination expand our understanding of how ubiquitination regulates synaptic plasticity.