Activity-Regulated Cytoskeleton-Associated Protein Controls AMPAR Endocytosis through a Direct Interaction with Clathrin-Adaptor Protein 2.
Activity-Regulated Cytoskeleton-Associated Protein Controls AMPAR Endocytosis through a Direct Interaction with Clathrin-Adaptor Protein 2.
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DOI：
10.1523/eneuro.0144-15.2016
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发表时间：
2016-05
期刊：
影响因子：
3.4
通讯作者：
Corrêa SA
中科院分区：
文献类型：
--
作者：
DaSilva LL;Wall MJ;P de Almeida L;Wauters SC;Januário YC;Müller J;Corrêa SA
活性调节的细胞骨架相关 (Arc) 蛋白通过促进 AMPA 受体 (AMPAR) 内吞作用来控制突触强度。在这里，我们证明 Arc 通过与网格蛋白适配器蛋白 2 (AP-2) 直接相互作用来靶向 AMPAR 内化。我们发现，从 C57BL/6 小鼠获得的分离海马神经元中 Arc 过度表达会降低细胞表面 AMPAR GluA1 亚基的密度，并降低 AMPAR 介导的微型 EPSC (mEPSC) 的幅度和整流。 Arc 突变可阻止 AP-2 相互作用，从而减少 Arc 介导的 GluA1 内吞作用，并消除 AMPAR 介导的 mEPSC 振幅和整流的降低。 AP-2 亚基 µ2 的耗尽会阻止 Arc 介导的 mEPSC 振幅降低，这种效应可以通过重新引入 µ2 来恢复。 Arc-AP-2 相互作用在稳态突触缩放中发挥着重要作用，因为由神经元活动慢性增加引起的 Arc 依赖性 mEPSC 振幅下降被 AP-2 耗竭所抑制。这些数据提供了一种机制来解释 Arc 的活性依赖性表达如何通过与内吞网格蛋白接头 AP-2 的直接相互作用来决定性地控制 AMPAR 在细胞表面的命运并调节突触强度。
The activity-regulated cytoskeleton-associated (Arc) protein controls synaptic strength by facilitating AMPA receptor (AMPAR) endocytosis. Here we demonstrate that Arc targets AMPAR to be internalized through a direct interaction with the clathrin-adaptor protein 2 (AP-2). We show that Arc overexpression in dissociated hippocampal neurons obtained from C57BL/6 mouse reduces the density of AMPAR GluA1 subunits at the cell surface and reduces the amplitude and rectification of AMPAR-mediated miniature-EPSCs (mEPSCs). Mutations of Arc, that prevent the AP-2 interaction reduce Arc-mediated endocytosis of GluA1 and abolish the reduction in AMPAR-mediated mEPSC amplitude and rectification. Depletion of the AP-2 subunit µ2 blocks the Arc-mediated reduction in mEPSC amplitude, an effect that is restored by reintroducing µ2. The Arc–AP-2 interaction plays an important role in homeostatic synaptic scaling as the Arc-dependent decrease in mEPSC amplitude, induced by a chronic increase in neuronal activity, is inhibited by AP-2 depletion. These data provide a mechanism to explain how activity-dependent expression of Arc decisively controls the fate of AMPAR at the cell surface and modulates synaptic strength, via the direct interaction with the endocytic clathrin adaptor AP-2.