Identification and characterization of uptake systems for cystine and cysteine in cultured astrocytes and neurons: Evidence for methylmercury‐targeted disruption of astrocyte transport

Shanker, Gouri; Aschner, Michael

doi:10.1002/jnr.10066

Cited by 102 publications

(46 citation statements)

References 47 publications

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“…Moreover, cystine uptake into cortical neurons ( Fig. 2c) was negligible, a finding in agreement with a report showing that neurons preferentially take up cysteine rather than cystine for glutathione biosynthesis (Shanker and Aschner, 2001).…”

Section: Inhibition Of System X Csupporting

confidence: 92%

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors

Chung¹,

Lyons²,

Nelson³

et al. 2005

J. Neurosci.

282

298

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Glial cells play an important role in sequestering neuronally released glutamate via Naϩ -dependent transporters. Surprisingly, these transporters are not operational in glial-derived tumors (gliomas). Instead, gliomas release glutamate, causing excitotoxic death of neurons in the vicinity of the tumor. We now show that glutamate release from glioma cells is an obligatory by-product of cellular cystine uptake via system x c Ϫ , an electroneutral cystine-glutamate exchanger. Cystine is an essential precursor for the biosynthesis of glutathione, a major redox regulatory molecule that protects cells from endogenously produced reactive oxygen species (ROS). Glioma cells, but not neurons or astrocytes, rely primarily on cystine uptake via system x c Ϫ for their glutathione synthesis. Inhibition of system x c Ϫ causes a rapid depletion of glutathione, and the resulting loss of ROS defense causes caspase-mediated apoptosis. Glioma cells can be rescued if glutathione status is experimentally restored or if glutathione is substituted by alternate cellular antioxidants, confirming that ROS are indeed mediators of cell death. We describe two potent drugs that permit pharmacological inhibition of system x c Ϫ . One of these drugs, sulfasalazine, is clinically used to treat inflammatory bowel disease and rheumatoid arthritis. Sulfasalazine was able to reduce glutathione levels in tumor tissue and slow tumor growth in vivo in a commonly used intracranial xenograft animal model for human gliomas when administered by intraperitoneal injection. These data suggest that inhibition of cystine uptake into glioma cells through the pharmacological inhibition of system x c Ϫ may be a viable therapeutic strategy with a Food and Drug Administration-approved drug already in hand.

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Section: Inhibition Of System X Csupporting

confidence: 92%

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors

Chung¹,

Lyons²,

Nelson³

et al. 2005

J. Neurosci.

282

298

View full text Add to dashboard Cite

show abstract

“…In this context, it should be noted that cultured astrocytes preferably obtain cysteine via import and subsequent reduction of cystine, but they are also capable of importing cysteine via system x AG Ϫ or the high-affinity glutamate transporters (Kranich et al, 1998;Shanker and Aschner, 2001). Accordingly, GSH content and viability of mature astrocytes was primarily unaffected by blocking x c Ϫ transport (Shih et al, 2003;Chung et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Cultured neurons lose the capacity of cystine uptake via system x c Ϫ during development (Murphy et al, 1990;Sagara et al, 1993;Dringen et al, 1999). Yet, neuronal GSH synthesis is indirectly supported by astrocytic GSH release, its cleavage to cysteinylglycine and cysteine, and neuronal cysteine uptake through glutamate transporter EAAC1 (Dringen et al, 1999;Shanker and Aschner, 2001;Chen and Swanson, 2003). The in vivo role of system x c Ϫ in maintaining GSH synthesis and redox balance in hippocampus, however, remains elusive.…”

Section: Introductionmentioning

confidence: 99%

Loss of System x_c⁻Does Not Induce Oxidative Stress But Decreases Extracellular Glutamate in Hippocampus and Influences Spatial Working Memory and Limbic Seizure Susceptibility

Bundel¹,

Schallier²,

Loyens³

et al. 2011

J. Neurosci.

168

195

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System x cϪ exchanges intracellular glutamate for extracellular cystine, giving it a potential role in intracellular glutathione synthesis and nonvesicular glutamate release. We report that mice lacking the specific xCT subunit of system x c Ϫ (xCT Ϫ/Ϫ ) do not have a lower hippocampal glutathione content, increased oxidative stress or brain atrophy, nor exacerbated spatial reference memory deficits with aging. Together these results indicate that loss of system x c Ϫ does not induce oxidative stress in vivo. Young xCT Ϫ/Ϫ mice did however display a spatial working memory deficit. Interestingly, we observed significantly lower extracellular hippocampal glutamate concentrations in xCT Ϫ/Ϫ mice compared to wild-type littermates. Moreover, intrahippocampal perfusion with system x c Ϫ inhibitors lowered extracellular glutamate, whereas the system x c Ϫ activator N-acetylcysteine elevated extracellular glutamate in the rat hippocampus. This indicates that system x c Ϫ may be an interesting target for pathologies associated with excessive extracellular glutamate release in the hippocampus. Correspondingly, xCT deletion in mice elevated the threshold for limbic seizures and abolished the proconvulsive effects of N-acetylcysteine. These novel findings sustain that system x c Ϫ is an important source of extracellular glutamate in the hippocampus. System x c Ϫ is required for optimal spatial working memory, but its inactivation is clearly beneficial to decrease susceptibility for limbic epileptic seizures.

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“…Glutamate is taken up by different glutamate transporters (Schanker and Aschner, 2001). Glutamate transporters are thought to play important roles in the termination of the glutaminergic synaptic transmission in the brain.…”

Section: Discussionmentioning

confidence: 99%

Plasma homocysteine concentration relates to the severity but not to the duration of Alzheimer's disease

Nilsson

Gustafson

Hultberg

2004

Int J Geriat Psychiatry

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Identification and characterization of uptake systems for cystine and cysteine in cultured astrocytes and neurons: Evidence for methylmercury‐targeted disruption of astrocyte transport

Cited by 102 publications

References 47 publications

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors

Loss of System x_c⁻Does Not Induce Oxidative Stress But Decreases Extracellular Glutamate in Hippocampus and Influences Spatial Working Memory and Limbic Seizure Susceptibility

Plasma homocysteine concentration relates to the severity but not to the duration of Alzheimer's disease

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Identification and characterization of uptake systems for cystine and cysteine in cultured astrocytes and neurons: Evidence for methylmercury‐targeted disruption of astrocyte transport

Cited by 102 publications

References 47 publications

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors

Loss of System xc−Does Not Induce Oxidative Stress But Decreases Extracellular Glutamate in Hippocampus and Influences Spatial Working Memory and Limbic Seizure Susceptibility

Plasma homocysteine concentration relates to the severity but not to the duration of Alzheimer's disease

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Loss of System x_c⁻Does Not Induce Oxidative Stress But Decreases Extracellular Glutamate in Hippocampus and Influences Spatial Working Memory and Limbic Seizure Susceptibility