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Ammonia induces autophagy through Dopamine receptor D3 and MTOR

Research output: Contribution to journalArticlepeer-review

Zhiyuan Li, Xinmiao Ji, Wenchao Wang, Juanjuan Liu, Xiaofei Liang, Hong Wu, Jing Liu, Ulrike S. Eggert, Qingsong Liu, Xin Zhang

Original languageEnglish
Article numbere0153526
JournalPL o S One
Volume11
Issue number4
DOIs
Accepted/In press30 Mar 2016
Published14 Apr 2016

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  • journal.pone.0153526

    journal.pone.0153526.PDF, 7.21 MB, application/pdf

    Uploaded date:12 May 2016

    Version:Final published version

    Licence:CC BY

King's Authors

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.

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