Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Augusta University, CA3008, 1120 15th Street, Augusta, GA, 30912, USA.
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
Mol Neurobiol. 2018 Aug;55(8):6215-6226. doi: 10.1007/s12035-017-0836-4. Epub 2017 Dec 27.
Synapse-associated protein 102 (SAP102) is a scaffolding protein highly expressed early in development and plays a critical role in mediating glutamate receptor trafficking during synaptogenesis. Mutations in human SAP102 have been reported to cause intellectual disability, which is thought to be due to mislocalization of the mutant protein. However, little is known about the regulation of SAP102 synaptic targeting. Here, we investigate the role of phosphorylation of SAP102 in regulating its synaptic targeting. Previous studies have shown that synaptic targeting of SAP102 is regulated by C-terminal splicing. We now identify a phosphorylation site, serine 632, within the C-terminal alternatively spliced region, which is phosphorylated by casein kinase II (CK2). We show that Ser632 on SAP102 is phosphorylated in vitro, in heterologous cells, and in neurons. Moreover, we demonstrate that synaptic enrichment of SAP102 is increased by Ser632 phosphorylation. Consistently, elevation of synaptic activity that suppresses Ser632 phosphorylation reduces synaptic enrichment of SAP102. Furthermore, the mobility of SAP102 is decreased by Ser632 phosphorylation. Therefore, not only SAP102 synaptic targeting but also its mobility is regulated by Ser632 phosphorylation. These data provide evidence for a novel mechanism in regulating SAP102 function and glutamate receptor trafficking.
突触相关蛋白 102（SAP102）是一种支架蛋白，在发育早期高度表达，在突触发生过程中谷氨酸受体运输中发挥关键作用。人类 SAP102 的突变已被报道导致智力障碍，这被认为是由于突变蛋白的定位错误。然而，关于 SAP102 突触靶向的调节知之甚少。在这里，我们研究了 SAP102 磷酸化在调节其突触靶向中的作用。先前的研究表明，SAP102 的突触靶向受 C 端剪接调节。我们现在确定了 C 端选择性剪接区域内的一个磷酸化位点丝氨酸 632，它被酪蛋白激酶 II（CK2）磷酸化。我们表明 SAP102 上的 Ser632 在体外、异源细胞中和神经元中被磷酸化。此外，我们证明 SAP102 的突触富集通过 Ser632 磷酸化增加。一致地，抑制 Ser632 磷酸化的突触活动升高会降低 SAP102 的突触富集。此外，SAP102 的迁移率通过 Ser632 磷酸化降低。因此，SAP102 的突触靶向及其迁移率均受 Ser632 磷酸化调节。这些数据为调节 SAP102 功能和谷氨酸受体运输提供了一种新的机制证据。
