title: Glutamate induces autophagy via the two-pore channels in neural cells.
abstract: NAADP (nicotinic acid adenine dinucleotide phosphate) has been proposed as a second messenger for glutamate in neuronal and glial cells via the activation of the lysosomal Ca2+ channels TPC1 and TPC2. However, the activities of glutamate that are mediated by NAADP remain unclear. In this study, we evaluated the effect of glutamate on autophagy in astrocytes at physiological, non-toxic concentration. We found that glutamate induces autophagy at similar extent as NAADP. By contrast, the NAADP antagonist NED-19 or SiRNA-mediated inhibition of TPC1/2 decreases autophagy induced by glutamate, confirming a role for NAADP in this pathway. The involvement of TPC1/2 in glutamate-induced autophagy was also confirmed in SHSY5Y neuroblastoma cells. Finally, we show that glutamate leads to a NAADP-dependent activation of AMPK, which is required for autophagy induction, while mTOR activity is not affected by this treatment. Taken together, our results indicate that glutamate stimulates autophagy via NAADP/TPC/AMPK axis, providing new insights of how Ca2+ signalling glutamate-mediated can control the cell metabolism in the central nervous system.
authors.affiliation: Department of Pharmacology, Federal University of São Paulo, (UNIFESP), São Paulo, Brazil.
authors.forename: Gustavo J S
authors.initials: GJ
authors.lastname: Pereira
authors.affiliation: Department of Biology, University of Rome "Tor Vergata", Rome, Italy.|Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases IRCCS 'Lazzaro Spallanzani', Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Antonioli
authors.affiliation: Department of Pharmacology, Federal University of São Paulo, (UNIFESP), São Paulo, Brazil.
authors.forename: Hanako
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Department of Pharmacology, Federal University of São Paulo, (UNIFESP), São Paulo, Brazil.
authors.forename: Rodrigo P
authors.initials: RP
authors.lastname: Ureshino
authors.affiliation: Department of Pharmacology, Federal University of São Paulo, (UNIFESP), São Paulo, Brazil.
authors.forename: Aline R
authors.initials: AR
authors.lastname: Nascimento
authors.affiliation: Department of Pharmacology, Federal University of São Paulo, (UNIFESP), São Paulo, Brazil.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bincoletto
authors.affiliation: Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases IRCCS 'Lazzaro Spallanzani', Rome, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Vescovo
authors.affiliation: Department of Biology, University of Rome "Tor Vergata", Rome, Italy.|Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases IRCCS 'Lazzaro Spallanzani', Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
authors.affiliation: Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases IRCCS 'Lazzaro Spallanzani', Rome, Italy.|Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Lecce, Italy.
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fimia
authors.affiliation: Department of Pharmacology, Federal University of São Paulo, (UNIFESP), São Paulo, Brazil.
authors.forename: Soraya S
authors.initials: SS
authors.lastname: Smaili
mesh_terms: D001253:Astrocytes / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D018613:Microscopy, Confocal; D009249:NADP / Q000031:analogs & derivatives / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000097903:Two-Pore Channels
chemical_list: D015220:Calcium Channels; D018698:Glutamic Acid; D009249:NADP; C407357:TPCN1 protein, human; D000097903:Two-Pore Channels; C530224:TPCN2 protein, human; C024376:NAADP
keywords: AMPK; NAADP; autophagy; glutamate; two-pore channels