AMPA Receptor Signaling through BRAG2 and Arf6 Critical for Long-Term Synaptic Depression
AMPA Receptor Signaling through BRAG2 and Arf6 Critical for Long-Term Synaptic Depression
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DOI：
10.1016/j.neuron.2010.05.003
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发表时间：
2010-06-10
期刊：
影响因子：
16.2
通讯作者：
Kornau, Hans-Christian
中科院分区：
文献类型：
--
作者：
Scholz, Ralf;Berberich, Sven;Kornau, Hans-Christian
中枢神经系统突触通过活动依赖性的改变来支持学习和记忆。长期抑制（LTD）反映了基于靶向网格蛋白介导的内吞作用的突触AMPA受体含量的持续减少。在这里，我们报告了一种电流独立形式的AMPA受体信号，这是LTD的基础。我们发现AMPA受体直接通过GluA2亚基与突触蛋白BRAG2相互作用，后者作为鸟嘌呤核苷酸交换因子（GEF）用于涂层募集GTPase Arf6。brag2介导的催化作用由配体结合和GluA2酪氨酸磷酸化控制，在LTD诱导下激活Arf6内化突触AMPA受体。此外，在成熟的海马CA1锥体神经元中，急性阻断GluA2-BRAG2相互作用和靶向删除BRAG2可阻止ca3 -CA1细胞突触的LTD，无论其诱导途径如何。我们得出结论，AMPA受体触发的brag2介导的Arf6激活是不同形式的LTD的收敛步骤，从而为内吞货物控制囊泡形成提供了重要机制。
Central nervous system synapses undergo activity-dependent alterations to support learning and memory. Long-term depression (LTD) reflects a sustained reduction of the synaptic AMPA receptor content based on targeted clathrin-mediated endocytosis. Here we report a current-independent form of AMPA receptor signaling, fundamental for LTD. We found that AMPA receptors directly interact via the GluA2 subunit with the synaptic protein BRAG2, which functions as a guanine-nucleotide exchange factor (GEF) for the coat-recruitment GTPase Arf6. BRAG2-mediated catalysis, controlled by ligand-binding and tyrosine phosphorylation of GluA2, activates Arf6 to internalize synaptic AMPA receptors upon LTD induction. Furthermore, acute blockade of the GluA2-BRAG2 interaction and targeted deletion of BRAG2 in mature hippocampal CA1 pyramidal neurons prevents LTD in CA3-to-CA1 cell synapses, irrespective of the induction pathway. We conclude that BRAG2-mediated Arf6 activation triggered by AMPA receptors is the convergent step of different forms of LTD, thus providing an essential mechanism for the control of vesicle formation by endocytic cargo.