Anchoring and synaptic stability of PSD-95 is driven by ephrin-B3.
Anchoring and synaptic stability of PSD-95 is driven by ephrin-B3.
复制标题
DOI：
10.1038/nn.4140
复制
发表时间：
2015-11
影响因子：
25
通讯作者：
Dalva MB
中科院分区：
文献类型：
--
作者：
Hruska M;Henderson NT;Xia NL;Le Marchand SJ;Dalva MB
通过膜相关鸟苷酸激酶（MAGUK）蛋白在兴奋性突触处组织信号复合物调节突触发育、可塑性、衰老和疾病。MAGUK家族蛋白的翻译后修饰可以驱动其膜定位，但目前还不清楚这些细胞内蛋白如何靶向突触接触位点。在这里，我们使用超分辨率成像，生物化学方法和体内模型表明，跨突触组织蛋白ephrin-B3控制PSD-95的突触定位和稳定性，并通过对ephrin-B3（S332）上一个新的MAPK依赖性磷酸化位点的负调节将这些事件与神经元活动的变化联系起来。未磷酸化的肝配蛋白-B3在突触处富集，与突触处的PSD-95直接相互作用并稳定PSD-95。活性诱导的S332磷酸化使ephrin-B3从突触分散，阻止与PSD-95的相互作用，并增强PSD-95的周转。因此，ephrin-B3指定PSD-95的突触定位，并可能将PSD-95的突触稳定性与神经元活性的变化联系起来。
Organization of signaling complexes at excitatory synapses by Membrane Associated Guanylate Kinase (MAGUK) proteins regulates synapse development, plasticity, senescence, and disease. Post-translational modification of MAGUK family proteins can drive their membrane localization, yet it is unclear how these intracellular proteins are targeted to sites of synaptic contact. Here we show using super-resolution imaging, biochemical approaches, and in vivo models that the trans-synaptic organizing protein, ephrin-B3, controls the synaptic localization and stability of PSD-95 and links these events to changes in neuronal activity via negative regulation of a novel MAPK-dependent phosphorylation site on ephrin-B3 (S332). Unphosphorylated ephrin-B3 is enriched at synapses, interacts directly with and stabilizes PSD-95 at synapses. Activity induced phosphorylation of S332 disperses ephrin-B3 from synapses, prevents the interaction with, and enhances the turnover of PSD-95. Thus, ephrin-B3 specifies the synaptic localization of PSD-95 and likely links the synaptic stability of PSD-95 to changes in neuronal activity.