Orexin/hypocretin activates mTOR complex 1 (mTORC1) via an Erk/Akt-independent and calcium-stimulated lysosome v-ATPase pathway

Zhiqiang Wang, Shimeng Liu, Miyo Kakizaki, Yuuki Hirose, Yukiko Ishikawa, Hiromasa Funato, Masashi Yanagisawa, Yonghao Yu, Qinghua Liu

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The lack of the neuropeptide orexin, also known as hypocretin, results in narcolepsy, a chronic sleep disorder characterized by frequent sleep/cataplexy attacks and rapid eye movement sleep abnormalities. However, the downstream pathways of orexin signaling are not clearly understood. Here, we show that orexin activates the mTOR pathway, a central regulator of cell growth and metabolism, in the mouse brain and multiple recombinant cell lines that express the G protein-coupled receptors (GPCRs), orexin 1 receptor (OX1R) or orexin 2 receptor (OX2R). This orexin/GPCR-stimulated mTOR activation is sensitive to rapamycin, an inhibitor of mTOR complex 1 (mTORC1) but is independent of two well known mTORC1 activators, Erk and Akt. Rather, our studies indicate that orexin activates mTORC1 via extracellular calcium influx and the lysosome pathway involving v-ATPase and Rag GTPases. Moreover, a cytoplasmic calcium transient is sufficient to mimic orexin/GPCR signaling to mTORC1 activation in a v-ATPasedependent manner. Together, our studies suggest that the mTORC1 pathway functions downstream of orexin/GPCR signaling, which plays a crucial role in many physiological and metabolic processes.

Original languageEnglish (US)
Pages (from-to)31950-31959
Number of pages10
JournalJournal of Biological Chemistry
Volume289
Issue number46
DOIs
StatePublished - Nov 14 2014

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G-Protein-Coupled Receptors
Lysosomes
Adenosine Triphosphatases
Orexin Receptors
Calcium
Sleep
Chemical activation
Cataplexy
Physiological Phenomena
Narcolepsy
Eye movements
GTP Phosphohydrolases
REM Sleep
Cell growth
Sirolimus
Neuropeptides
Metabolism
Brain
Cells
Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Orexin/hypocretin activates mTOR complex 1 (mTORC1) via an Erk/Akt-independent and calcium-stimulated lysosome v-ATPase pathway. / Wang, Zhiqiang; Liu, Shimeng; Kakizaki, Miyo; Hirose, Yuuki; Ishikawa, Yukiko; Funato, Hiromasa; Yanagisawa, Masashi; Yu, Yonghao; Liu, Qinghua.

In: Journal of Biological Chemistry, Vol. 289, No. 46, 14.11.2014, p. 31950-31959.

Research output: Contribution to journalArticle

Wang, Zhiqiang ; Liu, Shimeng ; Kakizaki, Miyo ; Hirose, Yuuki ; Ishikawa, Yukiko ; Funato, Hiromasa ; Yanagisawa, Masashi ; Yu, Yonghao ; Liu, Qinghua. / Orexin/hypocretin activates mTOR complex 1 (mTORC1) via an Erk/Akt-independent and calcium-stimulated lysosome v-ATPase pathway. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 46. pp. 31950-31959.
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