Role of neuronal glutamate transporter in the cysteine uptake and intracellular glutathione levels in cultured cortical neurons

Himi, Toshiyuki; Ikeda, Masayuki; Yasuhara, Tadashi; Nishida, Motohiro; Morita, I.

doi:10.1007/s00702-003-0049-z

Cited by 93 publications

(64 citation statements)

References 34 publications

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“…Neurons express only ASCT1, while astrocytes express both ASCT1 and ASCT2 (51). In neurons, cysteine uptake is not suppressed by system ASC substrates, but is suppressed by EAAT substrates (52,53). System ASC thus appears to play a minor role in neuronal cysteine uptake (48,52).…”

Section: Cysteine Uptakementioning

confidence: 99%

“…In particular, EAAC1 can transport cysteine at a rate comparable to that of glutamate with an affinity 10 -20-fold higher than that of GLAST or GLT-1 (76). Partial knock-down of EAAC1 resulted in approximately 20% decreases in cysteine uptake and the GSH contents of cultured neurons (53). Recently, another study demonstrated EAAC1 deficient mice to show 30% -40% decreases in brain GSH contents, increased oxidant levels, and increased vulnerability to oxidative stress (16).…”

Section: Eaatsmentioning

confidence: 99%

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Regulation of Neuronal Glutathione Synthesis

2008

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Abstract. The brain is among the major organs generating large amounts of reactive oxygen species and is especially susceptible to oxidative stress. Glutathione (GSH) plays critical roles as an antioxidant, enzyme cofactor, cysteine storage form, the major redox buffer, and a neuromodulator in the central nervous system. GSH deficiency has been implicated in neurodegenerative diseases. GSH is a tripeptide comprised of glutamate, cysteine, and glycine. Cysteine is the rate-limiting substrate for GSH synthesis within neurons. Most neuronal cysteine uptake is mediated by sodium-dependent excitatory amino acid transporter (EAAT) systems, known as excitatory amino acid carrier 1 (EAAC1). Previous studies demonstrated EAAT is vulnerable to oxidative stress, leading to impaired function. A recent study found EAAC1-deficient mice to have decreased brain GSH levels and increased susceptibility to oxidative stress. The function of EAAC1 is also regulated by glutamate transporter associated protein 3-18. This review focuses on the mechanisms underlying GSH synthesis, especially those related to neuronal cysteine transport via EAAC1, as well as on the importance of GSH functions against oxidative stress.

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Section: Cysteine Uptakementioning

confidence: 99%

Section: Eaatsmentioning

confidence: 99%

Regulation of Neuronal Glutathione Synthesis

2008

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“…Excitatory amino acid transporter type 3 (EAAT3), also known as EAAC1, provides the primary route of cysteine uptake by neurons, and a knockout of EAAT3 leads to significantly reduced neuronal GSH levels and neurodegeneration (Chen and Swanson, 2003;Himi et al, 2003;Aoyama et al, 2006). Under basal conditions, EAAT3 is primarily sequestered in intracellular vesicles, with only about 20% of the transporter being localized at the cell surface.…”

Section: Introductionmentioning

confidence: 99%

Morphine Induces Redox-Based Changes in Global DNA Methylation and Retrotransposon Transcription by Inhibition of Excitatory Amino Acid Transporter Type 3–Mediated Cysteine Uptake

Trivedi

Shah

Hodgson

et al. 2014

Molecular Pharmacology

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Canonically, opioids influence cells by binding to a G proteincoupled opioid receptor, initiating intracellular signaling cascades, such as protein kinase, phosphatidylinositol 3-kinase, and extracellular receptor kinase pathways. This results in several downstream effects, including decreased levels of the reduced form of glutathione (GSH) and elevated oxidative stress, as well as epigenetic changes, especially in retrotransposons and heterochromatin, although the mechanism and consequences of these actions are unclear. We characterized the acute and long-term influence of morphine on redox and methylation status (including DNA methylation levels) in cultured neuronal SH-SY5Y cells. Acting via m-opioid receptors, morphine inhibits excitatory amino acid transporter type 3-mediated cysteine uptake via multiple signaling pathways, involving different G proteins and protein kinases in a temporal manner. Decreased cysteine uptake was associated with decreases in both the redox and methylation status of neuronal cells, as defined by the ratios of GSH to oxidized forms of glutathione and S-adenosylmethionine to S-adenosylhomocysteine levels, respectively. Further, morphine induced global DNA methylation changes, including CpG sites in long interspersed nuclear elements (LINE-1) retrotransposons, resulting in increased LINE-1 mRNA. Together, these findings illuminate the mechanism by which morphine, and potentially other opioids, can influence neuronal-cell redox and methylation status including DNA methylation. Since epigenetic changes are implicated in drug addiction and tolerance phenomenon, this study could potentially extrapolate to elucidate a novel mechanism of action for other drugs of abuse.

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“…Ϫ/Ϫ mice It has been shown that EAAC1 is the primary route for cysteine uptake (Zerangue and Kavanaugh, 1996), and inhibitors of EAAC1 prevent neuronal GSH synthesis in the presence of extracellular cysteine (Chen and Swanson, 2003;Himi et al, 2003). Therefore, we investigated whether EAAC1 expression is influenced in PICK1 Ϫ/Ϫ mice.…”

Section: Surface Eaac1 Is Reduced In Pick1mentioning

confidence: 99%

Protein Interacting with C-Kinase 1 Deficiency Impairs Glutathione Synthesis and Increases Oxidative Stress via Reduction of Surface Excitatory Amino Acid Carrier 1

Wang

Zhou

et al. 2015

J. Neurosci.

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Protein interacting with C-kinase 1 (PICK1) has received considerable attention, because it interacts with a broad range of neurotransmitter receptors, transporters, and enzymes and thereby influences their localization and function in the CNS. Although it is suggested that putative partners of PICK1 are involved in neurological diseases such as schizophrenia, Parkinson's disease, chronic pain, and amyotrophic lateral sclerosis, the functions of PICK1 in neurological disorders are not clear. Here, we show that oxidative stress, which is tightly associated with neurological diseases, occurs in PICK1 Ϫ/Ϫ mice. The oxidation in PICK1 Ϫ/Ϫ mice was found selectively in neurons and was age dependent, leading to microglial activation and the release of inflammatory factors. Neurons in the cortex and hippocampus from PICK1 Ϫ/Ϫ mice showed increased vulnerability to oxidants and reduced capacity to metabolize reactive oxygen species (ROS); this was caused by reduced glutathione content and impaired cysteine transport. The dysregulated expression of glutathione was attributed to a decrease of the surface glutamate transporter excitatory amino acid carrier 1 (EAAC1). Overexpression of PICK1 could rescue the surface expression of EAAC1 and ameliorate the glutathione deficit in PICK1 Ϫ/Ϫ neurons. Finally, reduced surface EAAC1 was associated with defective Rab11 activity. Transfection with dominant-negative Rab11 effectively suppressed surface EAAC1 and increased ROS production. Together, these results indicate that PICK1 is a crucial regulator in glutathione homeostasis and may play important roles in oxidative stress and its associated neurodegenerative diseases.

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Role of neuronal glutamate transporter in the cysteine uptake and intracellular glutathione levels in cultured cortical neurons

Cited by 93 publications

References 34 publications

Regulation of Neuronal Glutathione Synthesis

Regulation of Neuronal Glutathione Synthesis

Morphine Induces Redox-Based Changes in Global DNA Methylation and Retrotransposon Transcription by Inhibition of Excitatory Amino Acid Transporter Type 3–Mediated Cysteine Uptake

Protein Interacting with C-Kinase 1 Deficiency Impairs Glutathione Synthesis and Increases Oxidative Stress via Reduction of Surface Excitatory Amino Acid Carrier 1

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