Zhang Wenbin, Zhang Jiaqi, Zhang Zhongqi, Cha Shuhan, Li Jiong, Chen Li, Wu Jiaming, Teng Jijun, Guo Guoqing, Zhang Jifeng
Department of Anatomy, Neuroscience Laboratory for Cognitive and Developmental Disorders, Medical College of Jinan University, Guangzhou, 510630, China.
Department of Surgery, The First Clinical Medical College, Jinan University, Guangzhou, 510630, China.
Mol Neurobiol. 2024 Aug;61(8):6045-6059. doi: 10.1007/s12035-024-03935-w. Epub 2024 Jan 24.
Surface trafficking of AMPA receptors (AMPARs) is one of the important mechanisms mediating synaptic plasticity which is essential for cognitive functions such as learning and memory. Spastin, as a novel binding partner for the AMPAR, has been reported to regulate AMPAR surface expression and synaptic function. Additionally, Spastin undergoes two posttranslational modifications, phosphorylation and SUMOylation, both of which are crucial for synaptic function. However, gaps exist in our knowledge of how Spastin phosphorylation cross-talks with its SUMOylation in the regulation of AMPAR surface expression and synaptic function. Here, we reported that deSUMOylation of Spastin at Lys427 increased the surface level of AMPAR GluA2 subunit, the amplitude and frequency of miniature excitatory synaptic currents (mEPSC), and facilitated the morphological maturation of dendritic spines in cultured hippocampal neurons. Further studies demonstrated that Spastin phosphorylation at Ser210 further increased the enhancement of GluA2 surface expression and synaptic function by deSUMOylated Spastin, while dephosphorylation had the opposite effect. Simultaneously, deSUMOylation at Lys427 significantly increased the promoting effect of Spastin phosphorylation on synaptic function. In conclusion, our study suggests that cooperative interactions between phosphorylated and deSUMOylated Spastin are novel pathways to enhance synaptic function.
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPAR）的表面转运是介导突触可塑性的重要机制之一，而突触可塑性对于学习和记忆等认知功能至关重要。据报道，痉挛素作为AMPAR的一种新型结合伴侣，可调节AMPAR的表面表达和突触功能。此外，痉挛素经历两种翻译后修饰，即磷酸化和小泛素样修饰蛋白化，这两种修饰对于突触功能都至关重要。然而，在痉挛素磷酸化如何与其小泛素样修饰蛋白化在调节AMPAR表面表达和突触功能方面相互作用的问题上，我们的认识还存在空白。在此，我们报道，痉挛素在赖氨酸427位点的去小泛素样修饰蛋白化增加了AMPAR GluA2亚基的表面水平、微小兴奋性突触电流（mEPSC）的幅度和频率，并促进了培养的海马神经元中树突棘的形态成熟。进一步的研究表明，痉挛素在丝氨酸210位点的磷酸化进一步增强了去小泛素样修饰蛋白化的痉挛素对GluA2表面表达和突触功能的增强作用，而去磷酸化则具有相反的效果。同时，赖氨酸427位点的去小泛素样修饰蛋白化显著增强了痉挛素磷酸化对突触功能的促进作用。总之，我们的研究表明，磷酸化和去小泛素样修饰蛋白化的痉挛素之间的协同相互作用是增强突触功能的新途径。
