Synaptic strength is altered during synaptic plasticity by controlling the number of AMPA receptors (AMPARs) at excitatory synapses. During long-term potentiation and synaptic upscaling, AMPARs are accumulated at synapses to increase synaptic strength. Neuronal activity leads to phosphorylation of AMPAR subunit GluA1 (also known as GRIA1) and subsequent elevation of GluA1 surface expression, either by an increase in receptor forward trafficking to the synaptic membrane or a decrease in receptor internalization. However, the molecular pathways underlying GluA1 phosphorylation-induced elevation of surface AMPAR expression are not completely understood. Here, we employ fluorescence recovery after photobleaching (FRAP) to reveal that phosphorylation of GluA1 serine 845 (S845) predominantly plays a role in receptor internalization, rather than forward trafficking, during synaptic plasticity. Notably, internalization of AMPARs depends upon the clathrin adaptor AP2, which recruits cargo proteins into endocytic clathrin-coated pits. In fact, we further reveal that an increase in GluA1 S845 phosphorylation upon two distinct forms of synaptic plasticity diminishes the binding of the AP2 adaptor, reducing internalization and resulting in elevation of GluA1 surface expression. We thus demonstrate a mechanism of GluA1 phosphorylation-regulated clathrin-mediated internalization of AMPARs.

中文翻译：

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AMPA 受体亚基 GluA1 的磷酸化调节网格蛋白介导的受体内化。

通过控制兴奋性突触处的 AMPA 受体 (AMPAR) 的数量来改变突触可塑性期间的突触强度。在长期增强和突触放大期间，AMPAR 在突触处积累以增加突触强度。神经元活动导致 AMPAR 亚基 GluA1（也称为 GRIA1）的磷酸化和随后的 GluA1 表面表达升高，通过增加向突触膜的受体向前运输或减少受体内化。然而，GluA1 磷酸化诱导的表面 AMPAR 表达升高的分子途径尚不完全清楚。在这里，我们采用光漂白后的荧光恢复 (FRAP) 来揭示 GluA1 丝氨酸 845 (S845) 的磷酸化主要在受体内化中起作用，在突触可塑性期间，而不是向前贩运。值得注意的是，AMPAR 的内化依赖于网格蛋白适配器 AP2，它将货物蛋白募集到内吞网格蛋白包被的凹坑中。事实上，我们进一步揭示，两种不同形式的突触可塑性增加 GluA1 S845 磷酸化会减少 AP2 接头的结合，减少内化并导致 GluA1 表面表达升高。因此，我们证明了 GluA1 磷酸化调节网格蛋白介导的 AMPAR 内化的机制。我们进一步揭示，两种不同形式的突触可塑性增加 GluA1 S845 磷酸化会减少 AP2 接头的结合，减少内化并导致 GluA1 表面表达升高。因此，我们证明了 GluA1 磷酸化调节网格蛋白介导的 AMPAR 内化的机制。我们进一步揭示，两种不同形式的突触可塑性增加 GluA1 S845 磷酸化会减少 AP2 接头的结合，减少内化并导致 GluA1 表面表达升高。因此，我们证明了 GluA1 磷酸化调节网格蛋白介导的 AMPAR 内化的机制。