Li Zhiyuan, Ji Xinmiao, Wang Wenchao, Liu Juanjuan, Liang Xiaofei, Wu Hong, Liu Jing, Eggert Ulrike S, Liu Qingsong, Zhang Xin
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
University of Science and Technology of China, Hefei, Anhui, P. R. China.
PLoS One. 2016 Apr 14;11(4):e0153526. doi: 10.1371/journal.pone.0153526. eCollection 2016.
Hyperammonemia is frequently seen in tumor microenvironments as well as in liver diseases where it can lead to severe brain damage or death. Ammonia induces autophagy, a mechanism that tumor cells may use to protect themselves from external stresses. However, how cells sense ammonia has been unclear. Here we show that culture medium alone containing Glutamine can generate milimolar of ammonia at 37 degrees in the absence of cells. In addition, we reveal that ammonia acts through the G protein-coupled receptor DRD3 (Dopamine receptor D3) to induce autophagy. At the same time, ammonia induces DRD3 degradation, which involves PIK3C3/VPS34-dependent pathways. Ammonia inhibits MTOR (mechanistic target of Rapamycin) activity and localization in cells, which is mediated by DRD3. Therefore, ammonia has dual roles in autophagy: one to induce autophagy through DRD3 and MTOR, the other to increase autophagosomal pH to inhibit autophagic flux. Our study not only adds a new sensing and output pathway for DRD3 that bridges ammonia sensing and autophagy induction, but also provides potential mechanisms for the clinical consequences of hyperammonemia in brain damage, neurodegenerative diseases and tumors.
高氨血症在肿瘤微环境以及肝脏疾病中经常出现，在这些情况下它可能导致严重的脑损伤或死亡。氨会诱导自噬，这是肿瘤细胞可能用来保护自己免受外部压力的一种机制。然而，细胞如何感知氨尚不清楚。在这里，我们表明，在没有细胞的情况下，仅含谷氨酰胺的培养基在37摄氏度时就能产生毫摩尔级的氨。此外，我们发现氨通过G蛋白偶联受体DRD3（多巴胺受体D3）发挥作用来诱导自噬。同时，氨会诱导DRD3降解，这涉及PIK3C3/VPS34依赖性途径。氨会抑制细胞中MTOR（雷帕霉素作用靶点）的活性和定位，这是由DRD3介导的。因此，氨在自噬中具有双重作用：一是通过DRD3和MTOR诱导自噬，另一个是提高自噬体pH值以抑制自噬流。我们的研究不仅为DRD3增加了一条连接氨感知和自噬诱导的新感知和输出途径，还为高氨血症在脑损伤、神经退行性疾病和肿瘤中的临床后果提供了潜在机制。
