Chen Bing, Zhao Ling, Li Xian, Ji Yun-Song, Li Na, Xu Xu-Feng, Chen Zhe-Yu
From the Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Number 44 Wenhua Xi Road, Jinan, Shandong 250012, China.
From the Department of Neurobiology, Shandong Provincial Key Laboratory of Mental Disorders, School of Medicine, Shandong University, Number 44 Wenhua Xi Road, Jinan, Shandong 250012, China
J Biol Chem. 2014 Jul 11;289(28):19556-69. doi: 10.1074/jbc.M114.567925. Epub 2014 May 28.
Nerve growth factor (NGF) promotes the survival, maintenance, and neurite outgrowth of sensory and sympathetic neurons, and the effects are mediated by TrkA receptor signaling. Thus, the cell surface location of the TrkA receptor is crucial for NGF-mediated functions. However, the regulatory mechanism underlying TrkA cell surface levels remains incompletely understood. In this study, we identified syntaxin 8 (STX8), a Q-SNARE protein, as a novel TrkA-binding protein. Overexpression and knockdown studies showed that STX8 facilitates TrkA transport from the Golgi to the plasma membrane and regulates the surface levels of TrkA but not TrkB receptors. Furthermore, STX8 modulates downstream NGF-induced TrkA signaling and, consequently, the survival of NGF-dependent dorsal root ganglia neurons. Finally, knockdown of STX8 in rat dorsal root ganglia by recombinant adeno-associated virus serotype 6-mediated RNA interference led to analgesic effects on formalin-induced inflammatory pain. These findings demonstrate that STX8 is a modulator of TrkA cell surface levels and biological functions.
神经生长因子（NGF）可促进感觉神经元和交感神经元的存活、维持及神经突生长，其作用由TrkA受体信号介导。因此，TrkA受体的细胞表面定位对于NGF介导的功能至关重要。然而，TrkA细胞表面水平的调控机制仍未完全明确。在本研究中，我们鉴定出Syntaxin 8（STX8），一种Q-SNARE蛋白，为新型TrkA结合蛋白。过表达和敲低实验表明，STX8促进TrkA从高尔基体向质膜的转运，并调节TrkA而非TrkB受体的表面水平。此外，STX8调节下游NGF诱导的TrkA信号传导，进而调节NGF依赖性背根神经节神经元的存活。最后，通过重组腺相关病毒血清型6介导的RNA干扰在大鼠背根神经节中敲低STX8，对福尔马林诱导的炎性疼痛产生镇痛作用。这些发现表明，STX8是TrkA细胞表面水平和生物学功能的调节因子。
