Glutamate induces autophagy via the two-pore channels in neural cells

Gustavo J S Pereira, Manuela Antonioli, Hanako Hirata, Rodrigo P. Ureshino, Aline R Nascimento, Claudia Bincoletto, Tiziana Vescovo, Mauro Piacentini, Gian Maria Fimia, Soraya S. Smaili

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalOncotarget
DOIs
Publication statusE-pub ahead of print - Dec 31 2016

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Autophagy
Glutamic Acid
AMP-Activated Protein Kinases
Second Messenger Systems
NAADP
Neuroblastoma
Neuroglia
Astrocytes
Central Nervous System

Keywords

  • Journal Article

Cite this

Pereira, G. J. S., Antonioli, M., Hirata, H., Ureshino, R. P., Nascimento, A. R., Bincoletto, C., ... Smaili, S. S. (2016). Glutamate induces autophagy via the two-pore channels in neural cells. Oncotarget. https://doi.org/10.18632/oncotarget.14404

Glutamate induces autophagy via the two-pore channels in neural cells. / Pereira, Gustavo J S; Antonioli, Manuela; Hirata, Hanako; Ureshino, Rodrigo P.; Nascimento, Aline R; Bincoletto, Claudia; Vescovo, Tiziana; Piacentini, Mauro; Fimia, Gian Maria; Smaili, Soraya S.

In: Oncotarget, 31.12.2016.

Research output: Contribution to journalArticle

Pereira, Gustavo J S ; Antonioli, Manuela ; Hirata, Hanako ; Ureshino, Rodrigo P. ; Nascimento, Aline R ; Bincoletto, Claudia ; Vescovo, Tiziana ; Piacentini, Mauro ; Fimia, Gian Maria ; Smaili, Soraya S. / Glutamate induces autophagy via the two-pore channels in neural cells. In: Oncotarget. 2016.
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AU - Antonioli, Manuela

AU - Hirata, Hanako

AU - Ureshino, Rodrigo P.

AU - Nascimento, Aline R

AU - Bincoletto, Claudia

AU - Vescovo, Tiziana

AU - Piacentini, Mauro

AU - Fimia, Gian Maria

AU - Smaili, Soraya S.

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N2 - 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.

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