Immunocytochemical evidence for the presence of high levels of reduced glutathione in radial glial cells and horizontal cells in the rabbit retina

Pow, David V.; Crook, Denise K.

doi:10.1016/0304-3940(95)11657-i

Cited by 83 publications

(57 citation statements)

References 16 publications

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“…It has been reported that in retina, GSH is localized primarily to Müller cells and horizontal cells [39]. This study did however describe low level GSH in other retinal neurons.…”

Section: Discussioncontrasting

confidence: 81%

Expression of the cystine-glutamate exchanger (xc −) in retinal ganglion cells and regulation by nitric oxide and oxidative stress

et al. 2006

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Purpose-The cystine-glutamate transporter, system x c -, mediates the Na + -independent exchange of cystine into cells coupled to the efflux of intracellular glutamate. Within cells, cystine is reduced to cysteine, a component of glutathione, thus system x c -plays a critical role in glutathione homeostasis. Studies in brain had initially suggested that system x c -was present primarily in astrocytes and not neurons, but more recent work suggests that certain brain neurons have an active system x c -. In the retina, system x c -has been demonstrated in retinal Müller and RPE cells. Recent immunohistochemical work from our lab suggested that the two protein components of system x c -, xCT and 4F2hc, are present in ganglion cells of the intact retina. The purpose of this investigation was to determine whether system x c -was present in primary ganglion cells isolated from neonatal mouse retinas and, if so, to study its regulation by oxidative stress in a retinal ganglion cell line, RGC-5.Methods-The presence of xCT and 4F2hc in RGC-5 cells was established by RT-PCR, immunoblotting and immunohistochemistry and in primary mouse retinal ganglion cells by immunoblotting and immunohistochemistry; the function of the transporter in RGC-5 cells was established by measuring radiolabeled glutamate uptake in the absence of Na + . To assess regulation of system x c -by oxidative stress in ganglion cells, RGC-5 cells were incubated in the presence or absence of nitric oxide (NO) donors (3-nitroso-N-acetylpenicillamine (SNAP), Snitrosoglutathione (SNOG), or 3-morpholinosydnonimine hydrochloride (SIN-1) and reactive oxygen species (ROS) donors menadione sodium bisulfite, hydrogen peroxide and xanthine sodium salt/xanthine oxidase and system x c -was analyzed using functional assays, RT-PCR and immunoblotting.Results-RGC-5 cells and primary ganglion cells isolated from mouse retina express xCT and 4F2hc as demonstrated by RT-PCR, immunoblotting and immunohistochemistry. RGC-5 cells take up glutamate in the absence of Na + and this uptake was blocked by known inhibitors of system x c -, glutamate, cysteine, and cystine as well as quisqualic acid. Treatment of RGC-5 cells with NO donors and donors of ROS led to an increase in the functional activity of system x c -. Kinetic analysis of SNAP-treated RGC-5 cells compared to control cells showed that the increase was associated with an increase in the maximal velocity of the transporter with no significant change in the substrate affinity. Molecular analyses showed that the upregulation is associated with an increase in the expression of xCT with no detectable change in the expression of 4F2hc. Conclusions-RGC-5 cells and ganglion cells isolated from neonatal mice express the cystine/ glutamate transporter x c -(the light chain xCT and the heavy chain 4F2hc) as is evident from functional and molecular studies. Oxidative stress upregulates this transport system in RGC-5 cells and the process is associated with an increase in xCT mRNA and protein but no change in 4F2hc mRNA or...

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“…It has been reported that in retina, GSH is localized primarily to Müller cells and horizontal cells [39]. This study did however describe low level GSH in other retinal neurons.…”

Section: Discussioncontrasting

confidence: 81%

Expression of the cystine-glutamate exchanger (xc −) in retinal ganglion cells and regulation by nitric oxide and oxidative stress

et al. 2006

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“…A second retinal cell type in which system x c -has been investigated is the Mü ller glial cell. The GSH concentration in the retina is relatively high (1.2 lmol/g wet weight in freshly isolated rat retina) and, as demonstrated by immunohistochemistry with antibodies against GSH, much of the GSH is present in Mü ller cells (210). Indeed, Mü ller cells protect adjacent retinal neurons by providing GSH to neurons under ischemic conditions.…”

Section: Studies Of System X Cmentioning

confidence: 92%

The Cystine/Glutamate Antiporter System x_c⁻in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

Lewerenz

Hewett

Huang

et al. 2013

Antioxidants & Redox Signaling

763

655

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The antiporter system x c -imports the amino acid cystine, the oxidized form of cysteine, into cells with a 1:1 counter-transport of glutamate. It is composed of a light chain, xCT, and a heavy chain, 4F2 heavy chain (4F2hc), and, thus, belongs to the family of heterodimeric amino acid transporters. Cysteine is the rate-limiting substrate for the important antioxidant glutathione (GSH) and, along with cystine, it also forms a key redox couple on its own. Glutamate is a major neurotransmitter in the central nervous system (CNS). By phylogenetic analysis, we show that system x c -is a rather evolutionarily new amino acid transport system. In addition, we summarize the current knowledge regarding the molecular mechanisms that regulate system x c -, including the transcriptional regulation of the xCT light chain, posttranscriptional mechanisms, and pharmacological inhibitors of system x c -. Moreover, the roles of system x c -in regulating GSH levels, the redox state of the extracellular cystine/cysteine redox couple, and extracellular glutamate levels are discussed. In vitro, glutamate-mediated system x c -inhibition leads to neuronal cell death, a paradigm called oxidative glutamate toxicity, which has successfully been used to identify neuroprotective compounds. In vivo, xCT has a rather restricted expression pattern with the highest levels in the CNS and parts of the immune system. System x c -is also present in the eye. Moreover, an elevated expression of xCT has been reported in cancer. We highlight the diverse roles of system x c -in the regulation of the immune response, in various aspects of cancer and in the eye and the CNS. Antioxid. Redox Signal. 18, 522-555.

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“…In addition, the outer retina underlies circadian periods of hypoxia (dark) and hyperoxia (light) [147,148]; both increase the oxidative stress in the retinal tissue. Müller cells produce the antioxidant glutathione, a tripeptide synthesized from glutamate, cysteine and glycine [149,150,151,152]. In response to hypoxia, hypoglycemia and oxidative stress, glutathione is rapidly released from Müller cells and made available to the neurons [58,151,153].…”

Section: Malfunction Of Glutathione Synthesismentioning

confidence: 99%

Müller Glial Cells in Retinal Disease

Bringmann¹,

Wiedemann²

2011

Ophthalmologica

350

274

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Virtually all pathogenic stimuli activate Müller cells. Reactive Müller cells exert protective and toxic effects on photoreceptors and neurons. They contribute to oxidative stress and glutamate toxicity due to malfunctions of glutamate uptake and glutathione synthesis. Downregulation of potassium conductance disrupts transcellular potassium and water transport, resulting in neuronal hyperexcitability and edema. Protective effects of reactive Müller cells include upregulation of adenosine 5′-triphosphate (ATP)-degrading ectoenzymes, which enhances the extracellular availability of the neuroprotectant adenosine, abrogation of the osmotic release of ATP, which might protect retinal ganglion cells from apoptosis, and the release of antioxidants and neurotrophic factors. The dedifferentiation of reactive Müller cells to progenitor-like cells might have an impact on future therapeutic approaches. A better understanding of the gliotic mechanisms will be helpful in developing efficient therapeutic strategies aiming at increased protective and regenerative properties and decreased toxicity of reactive Müller cells.

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Immunocytochemical evidence for the presence of high levels of reduced glutathione in radial glial cells and horizontal cells in the rabbit retina

Cited by 83 publications

References 16 publications

Expression of the cystine-glutamate exchanger (xc −) in retinal ganglion cells and regulation by nitric oxide and oxidative stress

Expression of the cystine-glutamate exchanger (xc −) in retinal ganglion cells and regulation by nitric oxide and oxidative stress

The Cystine/Glutamate Antiporter System x_c⁻in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

Müller Glial Cells in Retinal Disease

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Immunocytochemical evidence for the presence of high levels of reduced glutathione in radial glial cells and horizontal cells in the rabbit retina

Cited by 83 publications

References 16 publications

Expression of the cystine-glutamate exchanger (xc −) in retinal ganglion cells and regulation by nitric oxide and oxidative stress

Expression of the cystine-glutamate exchanger (xc −) in retinal ganglion cells and regulation by nitric oxide and oxidative stress

The Cystine/Glutamate Antiporter System xc−in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

Müller Glial Cells in Retinal Disease

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The Cystine/Glutamate Antiporter System x_c⁻in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities