SAP102 Ser-386磷酸化对突触功能的调控及其在炎性疼痛中的作用

SAP102是一种在突触后致密区高表达的支架蛋白，在突触发育和可塑性变化过程中发挥关键作用。脊髓背角中NR2B型NMDAR的突触错误定位和功能异常是疼痛的发生和维持的重要机制，而NR2B型NMDAR在突触中的靶向定位依赖于NR2B亚基与SAP102的结合。目前，SAP102在脊髓背角痛觉调控方面的机制尚不清楚。我们的前期研究结果显示，SAP102 Ser386的磷酸化修饰参与脊髓背角的痛觉信息传递。而且，在炎性疼痛小鼠脊髓背角中，ERK与SAP102的结合能力增强，SAP102丝氨酸残基的磷酸化水平上升。提示，ERK/SAP102通路参与了脊髓背角痛觉调控。因此，本项目拟以此为切入点，将系统研究ERK/SAP102通路调控NR2B型NMDAR受体功能的具体机制，揭示ERK/SAP102/NR2B在脊髓背角痛觉调控中发挥的作用，开发有效多肽镇痛药物，为疼痛的治疗提供新的靶点和理论指导。

Synapse-associated protein 102 (SAP102), a scaffolding protein highly expressed in postsynaptic density, plays an important role in synaptogenesis and plasticity changes. The synaptic mislocalization and dysfunction of NR2B-containing NMDA receptors in the spinal dorsal horn are critical mechanisms for the occurrence and maintenance of inflammatory pain, and the targeted localization of NR2B-containing NMDA receptors in synapses depends on the binding of NR2B subunit and SAP102. However, the specific mechanism of SAP102 in the regulation of inflammatory pain in spinal dorsal horn is still unclear. Our previous study showed that phosphorylation of SAP102 Ser386 was involved in pain information transmission in spinal dorsal horn. In addition, the binding ability of ERK-SAP102 and the phosphorylation level of SAP102 serine residues were increased in inflammatory mice, suggesting that ERK/SAP102 pathway was involved in the regulation of inflammatory pain in spinal dorsal horn. Therefore, this project intends to take this as a starting point to systematically study the regulation mechanism of NR2B-containing NMDA receptors by ERK/SAP102 pathway, so as to provide new targets and theoretical guidance for the treatment of inflammatory pain.