Center for Molecular Neurobiology (ZMNH), University of Hamburg, Hamburg, Germany.
Neuron. 2010 Jun 10;66(5):768-80. doi: 10.1016/j.neuron.2010.05.003.
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.
中枢神经系统突触会发生活动依赖性改变，以支持学习和记忆。长时程抑制（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，我们报告了一种与电流无关的 AMPA 受体信号转导形式，这是 LTD 的基础。我们发现 AMPA 受体通过 GluA2 亚基直接与突触蛋白 BRAG2 相互作用，BRAG2 作为衔接蛋白募集 GTP 酶 Arf6 的鸟嘌呤核苷酸交换因子（GEF）。BRAG2 介导的催化作用受 GluA2 的配体结合和酪氨酸磷酸化的控制，在 LTD 诱导时激活 Arf6，从而内化突触 AMPA 受体。此外，在成熟海马 CA1 锥体神经元中，急性阻断 GluA2-BRAG2 相互作用和靶向删除 BRAG2，可防止 CA3 到 CA1 细胞突触中的 LTD，而与诱导途径无关。我们的结论是，由 AMPA 受体触发的 BRAG2 介导的 Arf6 激活是不同形式 LTD 的汇聚步骤，因此为内吞货物控制囊泡形成提供了一个必要的机制。
