Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure

Abstract Methamphetamine (METH) is a highly addictive psychostimulant that causes long-lasting effects in the brain and increases the risk of developing neurodegenerative diseases. The cellular and molecular effects of METH in the brain are functionally linked to alterations in glutamate levels. Des...

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Autores principales:	Bobby Jones, Muthukumar Balasubramaniam, Joseph J. Lebowitz, Anne Taylor, Fernando Villalta, Habibeh Khoshbouei, Carrie Grueter, Brad Grueter, Chandravanu Dash, Jui Pandhare
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c14ac558b3974efd995809baf00a9f90
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spelling	oai:doaj.org-article:c14ac558b3974efd995809baf00a9f902021-12-02T14:01:21ZActivation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure10.1038/s41598-020-80917-72045-2322https://doaj.org/article/c14ac558b3974efd995809baf00a9f902021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80917-7https://doaj.org/toc/2045-2322Abstract Methamphetamine (METH) is a highly addictive psychostimulant that causes long-lasting effects in the brain and increases the risk of developing neurodegenerative diseases. The cellular and molecular effects of METH in the brain are functionally linked to alterations in glutamate levels. Despite the well-documented effects of METH on glutamate neurotransmission, the underlying mechanism by which METH alters glutamate levels is not clearly understood. In this study, we report an essential role of proline biosynthesis in maintaining METH-induced glutamate homeostasis. We observed that acute METH exposure resulted in the induction of proline biosynthetic enzymes in both undifferentiated and differentiated neuronal cells. Proline level was also increased in these cells after METH exposure. Surprisingly, METH treatment did not increase glutamate levels nor caused neuronal excitotoxicity. However, METH exposure resulted in a significant upregulation of pyrroline-5-carboxylate synthase (P5CS), the key enzyme that catalyzes synthesis of proline from glutamate. Interestingly, depletion of P5CS by CRISPR/Cas9 resulted in a significant increase in glutamate levels upon METH exposure. METH exposure also increased glutamate levels in P5CS-deficient proline-auxotropic cells. Conversely, restoration of P5CS expression in P5CS-deficient cells abrogated the effect of METH on glutamate levels. Consistent with these findings, P5CS expression was significantly enhanced in the cortical brain region of mice administered with METH and in the slices of cortical brain tissues treated with METH. Collectively, these results uncover a key role of P5CS for the molecular effects of METH and highlight that excess glutamate can be sequestered for proline biosynthesis as a protective mechanism to maintain glutamate homeostasis during drug exposure.Bobby JonesMuthukumar BalasubramaniamJoseph J. LebowitzAnne TaylorFernando VillaltaHabibeh KhoshboueiCarrie GrueterBrad GrueterChandravanu DashJui PandhareNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bobby Jones Muthukumar Balasubramaniam Joseph J. Lebowitz Anne Taylor Fernando Villalta Habibeh Khoshbouei Carrie Grueter Brad Grueter Chandravanu Dash Jui Pandhare Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure
description	Abstract Methamphetamine (METH) is a highly addictive psychostimulant that causes long-lasting effects in the brain and increases the risk of developing neurodegenerative diseases. The cellular and molecular effects of METH in the brain are functionally linked to alterations in glutamate levels. Despite the well-documented effects of METH on glutamate neurotransmission, the underlying mechanism by which METH alters glutamate levels is not clearly understood. In this study, we report an essential role of proline biosynthesis in maintaining METH-induced glutamate homeostasis. We observed that acute METH exposure resulted in the induction of proline biosynthetic enzymes in both undifferentiated and differentiated neuronal cells. Proline level was also increased in these cells after METH exposure. Surprisingly, METH treatment did not increase glutamate levels nor caused neuronal excitotoxicity. However, METH exposure resulted in a significant upregulation of pyrroline-5-carboxylate synthase (P5CS), the key enzyme that catalyzes synthesis of proline from glutamate. Interestingly, depletion of P5CS by CRISPR/Cas9 resulted in a significant increase in glutamate levels upon METH exposure. METH exposure also increased glutamate levels in P5CS-deficient proline-auxotropic cells. Conversely, restoration of P5CS expression in P5CS-deficient cells abrogated the effect of METH on glutamate levels. Consistent with these findings, P5CS expression was significantly enhanced in the cortical brain region of mice administered with METH and in the slices of cortical brain tissues treated with METH. Collectively, these results uncover a key role of P5CS for the molecular effects of METH and highlight that excess glutamate can be sequestered for proline biosynthesis as a protective mechanism to maintain glutamate homeostasis during drug exposure.
format	article
author	Bobby Jones Muthukumar Balasubramaniam Joseph J. Lebowitz Anne Taylor Fernando Villalta Habibeh Khoshbouei Carrie Grueter Brad Grueter Chandravanu Dash Jui Pandhare
author_facet	Bobby Jones Muthukumar Balasubramaniam Joseph J. Lebowitz Anne Taylor Fernando Villalta Habibeh Khoshbouei Carrie Grueter Brad Grueter Chandravanu Dash Jui Pandhare
author_sort	Bobby Jones
title	Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure
title_short	Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure
title_full	Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure
title_fullStr	Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure
title_full_unstemmed	Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure
title_sort	activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c14ac558b3974efd995809baf00a9f90
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Activation of proline biosynthesis is critical to maintain glutamate homeostasis during acute methamphetamine exposure

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