title: Ammonia Induces Autophagy through Dopamine Receptor D3 and MTOR.
abstract: 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.
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
authors.forename: Xinmiao
authors.initials: X
authors.lastname: Ji
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
authors.forename: Ulrike S
authors.initials: US
authors.lastname: Eggert
authors.affiliation: 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.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
authors.forename: Xin
authors.identifier: http://orcid.org/0000-0002-3499-2189
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000641:Ammonia / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D003412:Cricetulus; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D059748:Proteolysis; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000641:Ammonia; D058546:Class III Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D050637:Receptors, Dopamine D3; D058570:TOR Serine-Threonine Kinases; C493593:DRD3 protein, human; C546842:MTOR protein, human