title: Orexin/hypocretin activates mTOR complex 1 (mTORC1) via an Erk/Akt-independent and calcium-stimulated lysosome v-ATPase pathway.
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-ATPase-dependent 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.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390,; College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Shimeng
authors.initials: S
authors.lastname: Liu
authors.affiliation: International Institute of Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan, and.
authors.forename: Miyo
authors.initials: M
authors.lastname: Kakizaki
authors.affiliation: International Institute of Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan, and.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Hirose
authors.affiliation: International Institute of Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan, and.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Ishikawa
authors.affiliation: International Institute of Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan, and; Department of Anatomy, Toho University School of Medicine, Tokyo 143-8540, Japan.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Funato
authors.affiliation: International Institute of Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan, and.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yanagisawa
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390,. Electronic address: yonghao.yu@utsouthwestern.edu.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390,; International Institute of Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Ibaraki 305-8575, Japan, and. Electronic address: qinghua.liu@utsouthwestern.edu.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D064446:Orexin Receptors / Q000378:metabolism*; D000068797:Orexins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: C501103:Cd200r1 protein, mouse; C578630:HCRTR1 protein, human; C578626:HCRTR2 protein, human; C497459:Hcrtr1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D025262:Vacuolar Proton-Translocating ATPases; D002118:Calcium
keywords: Calcium; G Protein-coupled Receptor (GPCR); Lysosome; Neuropeptide; OX1R Or OX2R; Orexin; Rag GTPase; Vacuolar ATPase; mTOR Complex (mTORC)