A key neuronal mechanism for adjusting excitatory synaptic strength is clathrin-mediated endocytosis of postsynaptic glutamate receptors (GluRs). The actin cytoskeleton is critical for clathrin-mediated endocytosis, yet we lack a mechanistic understanding of its interaction with the endocytic process and how it may be regulated. Here we show that F-actin in dendritic spines physically binds the synaptic nuclear envelope 1 gene product candidate plasticity gene 2 (CPG2) in a PKA-dependent manner, and that this association is required for synaptic GluR internalization. Mutating two PKA sites on CPG2 disrupts its cytoskeletal association, attenuating GluR endocytosis and affecting the efficacy of synaptic transmission in vivo. These results identify CPG2 as an F-actin binding partner that functionally mediates interaction of the spine cytoskeleton with postsynaptic endocytosis. Further, the regulation of CPG2/F-actin association by PKA provides a gateway for cellular control of synaptic receptor internalization through second messenger signaling pathways. Recent identification of human synaptic nuclear envelope 1 as a risk locus for bipolar disorder suggests that CPG2 could play a role in synaptic dysfunction underlying neuropsychiatric disease.

中文翻译：

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棘细胞骨架对谷氨酸受体内化的调节是由其与 CPG2 的 PKA 依赖性关联介导的。

调节兴奋性突触强度的关键神经元机制是网格蛋白介导的突触后谷氨酸受体 (GluR) 内吞作用。肌动蛋白细胞骨架对于网格蛋白介导的内吞作用至关重要，但我们对其与内吞过程的相互作用及其如何调节缺乏机制理解。在这里，我们显示树突棘中的 F-肌动蛋白以依赖于 PKA 的方式物理结合突触核信封 1 基因产品候选可塑性基因 2 (CPG2)，并且这种关联是突触 GluR 内化所必需的。CPG2 上的两个 PKA 位点突变会破坏其细胞骨架关联，减弱 GluR 内吞作用并影响体内突触传递的功效。这些结果将 CPG2 鉴定为 F-肌动蛋白结合伴侣，在功能上介导脊柱细胞骨架与突触后内吞作用的相互作用。此外，PKA 对 CPG2/F-肌动蛋白结合的调节为通过第二信使信号通路对突触受体内化进行细胞控制提供了途径。最近将人类突触核膜 1 鉴定为双相情感障碍的风险位点表明 CPG2 可能在神经精神疾病的突触功能障碍中发挥作用。