Syntaxin 8 Modulates the Post-synthetic Trafficking of the TrkA Receptor and Inflammatory Pain Transmission*

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. 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.