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

Autor:	Joseph J. Lebowitz, Anne Taylor, Muthukumar Balasubramaniam, Chandravanu Dash, Habibeh Khoshbouei, Jui Pandhare, Fernando Villalta, Carrie A. Grueter, Brad A. Grueter, Bobby Jones
Jazyk:	angličtina
Rok vydání:	2021
Předmět:	Male Proline Science Amphetamine-Related Disorders Excitotoxicity Glutamic Acid CHO Cells Neurotransmission Pharmacology Molecular neuroscience medicine.disease_cause Article Methamphetamine Mice chemistry.chemical_compound Cricetulus Downregulation and upregulation Glutamate homeostasis medicine Animals Homeostasis Humans Cerebral Cortex Neurons Multidisciplinary Glutamate receptor Meth Aldehyde Dehydrogenase chemistry Acute Disease Medicine Oxidoreductases medicine.drug
Zdroj:	Scientific Reports, Vol 11, Iss 1, Pp 1-16 (2021) Scientific Reports
ISSN:	2045-2322
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::683a0d77206d0e8014ffa34b23aa748c https://doaj.org/article/c14ac558b3974efd995809baf00a9f90 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.