Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System xc−) to Normal and Pathological Glutamatergic Signaling

Bridges, Richard J.; Lutgen, Victoria; Lobner, Doug; Baker, David L.

doi:10.1124/pr.110.003889

Cited by 183 publications

(159 citation statements)

References 372 publications

(469 reference statements)

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“…However, evidence also indicates that under particular circumstances, Sx c Ϫ can contribute to certain brain pathologies (for comprehensive review see Refs. [52][53][54]. The cytokine IL-1␤ also produces dichotomous results within the CNS (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

Interleukin 1β Regulation of the System xc− Substrate-specific Subunit, xCT, in Primary Mouse Astrocytes Involves the RNA-binding Protein HuR

Shi

Hewett

et al. 2016

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Interleukin 1β Regulation of the System xc− Substrate-specific Subunit, xCT, in Primary Mouse Astrocytes Involves the RNA-binding Protein HuR

Shi

Hewett

et al. 2016

Journal of Biological Chemistry

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“…Moreover, Behrens et al [45] and Sorce et al [50] previously reported increase in the level of the pro-inflammatory cytokine, interleukine-6 (IL-6) and superoxide producing enzyme, nicotinamide adenine denucleotide phosphate oxidase-2 (Nox-2) in the brain of rodents following repeated administration of ketamine, respectively. Therefore, the increased GSH concentration observed in this study by doxycycline might be mediated through prevention of microglial oxidative burst and inflammatory response elements, thereby enhancing microglial internalization of cysteine intracellularly [51], and cysteine uptake by the cysteine/glutamate exchange system to increase GSH synthesis [52].…”

Section: Discussionmentioning

confidence: 99%

Doxycycline Ameliorates Schizophrenia-Like Behaviors in Experimental Models in Mice by Targeting Underlying Oxidative Stress

Ben-Azu¹,

Omogbiya²,

Aderibigbe³

et al. 2016

JBBS

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Current evidences support the inhibition of oxidative and inflammatory signaling mechanisms in the treatment of schizophrenia; as cure for this disease still remains limited. Doxycycline is a tetracycline antibiotic (a minocycline congener) with strong antioxidant and anti-inflammatory properties, and better pharmacokinetic profiles. Preclinical evidence indicates that minocycline possesses antipsychotic properties. This present study was designed to evaluate the effect of doxycycline on schizophrenialike behaviors, as well as biomarkers of oxidative stress in mice brains. Noveltyinduced rearing (NIR) behavior was used to evaluate the tranquilizing effect of doxycycline (25 -200 mg/kg). The acute antipsychotic effects of doxycycline were assessed using apomorphine-induced stereotypy, ketamine-induced stereotypy, hyperlocomotion and enhanced immobility in forced swim test (FST). Catalepsy test was also employed to evaluate the extrapyramidal adverse effect of doxycycline in mice. The chronic antipsychotic effect of doxycycline was evaluated following oral administration of doxycycline in combination with ketamine (100 mg/kg) intraperitoneally for 10 days. Twenty four hours after the last administration, positive (locomotor activity), cognitive (Y-maze) and negative (FST) symptoms were assessed. Thereafter, levels of biomarkers of oxidative stress were evaluated in mice brains. Doxycycline significantly (P < 0.05) decreased NIR, inhibited stereotypy induced by apomorphine and ketamine. Additionally, doxycycline significantly (P < 0.05) prevented ketamineinduced hyperlocomotion, cognitive deficit and reduced enhanced-immobility by ketamine in mice. Furthermore, doxycycline decreased malondialdehyde concentrations in a dose-related manner. Moreover, doxycycline significantly (P < 0.05) prevented the decrease in glutathione, and increased activities of superoxide dismutase and catalase in brain tissues. The results from this study suggest that doxycycline 540ameliorated schizophrenic-like behaviors via mechanisms related to attenuation of oxidative stress in mouse brain.

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“…18,19) In addition, the Na + -independent and D/L-aspartate-insensitive system X c − , which is composed of xCT/Slc7a11 and 4F2hc/Slc3a2, has been reported to be involved in the influx transport of L-Glu at the plasma membrane of cells. [20][21][22] Regarding the plasma membrane transporters for L-Gln, ASCT2 accepts L-Gln, as well as L-Glu, as a substrate, 23) although ASCT1 does not recognize L-Gln.…”

mentioning

confidence: 99%

In Vitro Study of L-Glutamate and L-Glutamine Transport in Retinal Pericytes: Involvement of Excitatory Amino Acid Transporter 1 and Alanine–Serine–Cysteine Transporter 2

Akanuma

Zakoji

Kubo

et al. 2015

Biological & Pharmaceutical Bulletin

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L-Glutamate (L-Glu) is known to be a relaxant of pericytes and to induce changes in microcirculatory hemodynamics. Since the concentration of L-Glu which induces the dilation of retinal capillaries is reported to be high compared with the estimated concentration in the retinal interstitial fluid, it is hypothesized that some systems involving concentrative L-Glu release are present in retinal pericytes. The purpose of this study was to investigate the existence of L-Glu-storing systems, which contribute to autocrine L-Glu release, in retinal pericytes using conditionally immortalized rat retinal pericytes (TR-rPCT1 Key words excitatory amino acid transporter; L-glutamate; retinal pericyte; alanine-serine-cysteine transporter; L-glutamine Retinal pericytes reside within the basal lamina of retinal capillaries and communicate with the retinal capillary endothelial cells which form the blood-retinal barrier (BRB). 1,2)It is known that the contraction and relaxation of pericytes which are induced by physiological factors leads to a change in the diameter of the capillaries. [3][4][5] Because it has been reported that the diameter of capillaries in the central nervous system (CNS) affects the blood flow rate in the capillaries and, thus, the exchange of some compounds between the circulating blood and retina, 6) it is very important to identify the regulatory mechanisms governing the contraction and relaxation of retinal pericytes.L-Glutamate (L-Glu) is known as a relaxant of pericytes and Peppiatt et al. have reported that L-Glu treatment induces dilation of the retinal capillaries. 7) Regarding the mechanism for the L-Glu-induced dilation of retinal capillaries, it has been proposed that L-Glu induces the production of nitric oxide (NO), a relaxant of the cells, and inhibits Ca 2+ influx in retinal pericytes, thereby relaxing the pericytes. 7,8) An in vitro analysis has indicated that this L-Glu-induced NO production occurs in the presence of L-Glu at a concentration of more than 1 mM. 8) In addition, the dilation of retinal capillaries accompanied with pericytes was induced by treatment with 500 µM L-Glu.7) The compounds between the retinal interstitial fluid (ISF) and vitreous humor are considered to be freely exchangeable, and the concentration of L-Glu in the vitreous humor has been reported to be 444 µM in rats.9) Because the L-Glu level in the retinal ISF seems to be low compared with the concentration which induces dilation of the retinal capillaries and relaxation in the pericytes, it is possible that some mechanisms for concentrative L-Glu release are present in retinal pericytes and/or the cells surrounded by the pericytes. In neuronal cells, the packing of L-Glu into synaptic vesicles up to concentrations as high as 100 mM and exocytotic release of L-Glu in the vesicles into the synaptic cleft have been reported. [10][11][12] It has also been reported that the uptake of L-Glu from the cytoplasm of neurons into synaptic vesicles involves the vesicular L-Glu transporters (VGLUTs) which belong to the so...

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Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System x_c⁻) to Normal and Pathological Glutamatergic Signaling

Cited by 183 publications

References 372 publications

Interleukin 1β Regulation of the System xc− Substrate-specific Subunit, xCT, in Primary Mouse Astrocytes Involves the RNA-binding Protein HuR

Interleukin 1β Regulation of the System xc− Substrate-specific Subunit, xCT, in Primary Mouse Astrocytes Involves the RNA-binding Protein HuR

Doxycycline Ameliorates Schizophrenia-Like Behaviors in Experimental Models in Mice by Targeting Underlying Oxidative Stress

<i>In Vitro</i> Study of L-Glutamate and L-Glutamine Transport in Retinal Pericytes: Involvement of Excitatory Amino Acid Transporter 1 and Alanine–Serine–Cysteine Transporter 2

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