Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Department of Neuroscience and Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Cell Res. 2022 Oct;32(10):914-930. doi: 10.1038/s41422-022-00697-9. Epub 2022 Jul 18.
In response to stimuli, the immediate early gene product Arc can acutely down-regulate synaptic strength by removing AMPA receptors (AMPARs) from synapses and thus regulate synaptic plasticity. How Arc, a scaffold protein, can specifically facilitate synaptic removal of AMPARs is unknown. We found that Arc directly antagonizes with PSD-95 in binding to TARPs, which are the auxiliary subunits of AMPARs. Arc, in a highly concentration-sensitive manner, acutely disperses TARPs from the postsynaptic density (PSD) condensate formed via phase separation. TARPs with the Ser residue in the "P-S-Y"-motif of its tail phosphorylated are completely refractory from being dispersed by Arc, suggesting that Arc cannot displace AMPARs from PSDs in active synapses. Conversely, strengthening the interaction between Arc and TARPs enhances Arc's capacity in weakening synapses. Thus, Arc can specifically and effectively modulate synaptic AMPAR clustering via modulating PSD phase separation. Our study further suggests that activity-dependent, bi-directional modulation of PSD condensate formation/dispersion represents a general regulatory mechanism for synaptic plasticity.
在受到刺激时，早期基因产物 Arc 可以通过从突触中去除 AMPA 受体（AMPARs）来迅速下调突触强度，从而调节突触可塑性。Arc（一种支架蛋白）如何特异性地促进 AMPAR 从突触中的去除尚不清楚。我们发现 Arc 可以直接与 PSD-95 竞争与 TARPs（AMPAR 的辅助亚基）结合。Arc 以高度浓度敏感的方式，迅速将 TARPs 从通过相分离形成的突触后密度（PSD）凝聚体中分散开。其尾部的“P-S-Y”基序中的丝氨酸残基发生磷酸化的 TARPs 完全不能被 Arc 分散，这表明 Arc 不能将 AMPAR 从活性突触的 PSD 中置换出来。相反，增强 Arc 和 TARPs 之间的相互作用会增强 Arc 减弱突触的能力。因此，Arc 可以通过调节 PSD 相分离来特异性和有效地调节突触 AMPAR 聚类。我们的研究进一步表明，PSD 凝聚体形成/分散的活性依赖性双向调节代表了突触可塑性的一般调节机制。
