The role of amino acid transporters in GSH synthesis in the blood–brain barrier and central nervous system

Valdovinos-Flores, Cesar; Gonsebatt, María E.

doi:10.1016/j.neuint.2012.05.019

Cited by 44 publications

(34 citation statements)

References 191 publications

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“…In vertebrates, GGT1 is expressed at the luminal surface of the BBB where it functions in both amino acid transport and the regulation of glutathione levels (and thus the detoxification processes involving GSTs) (Courtay et al, 1992; Hawkins et al, 2006). An alternative explanation might be that the surface glia express GGT1 similar to astroctyes, where they function to facilitate glutathione synthesis in neurons (Valdovinos-Flores and Gonsebatt, 2012). Another striking result in Table 9 is the conservation of insulin signaling at the mouse and fly BBBs.…”

Section: Resultsmentioning

confidence: 99%

The Drosophila surface glia transcriptome: evolutionary conserved blood-brain barrier processes

et al. 2014

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Central nervous system (CNS) function is dependent on the stringent regulation of metabolites, drugs, cells, and pathogens exposed to the CNS space. Cellular blood-brain barrier (BBB) structures are highly specific checkpoints governing entry and exit of all small molecules to and from the brain interstitial space, but the precise mechanisms that regulate the BBB are not well understood. In addition, the BBB has long been a challenging obstacle to the pharmacologic treatment of CNS diseases; thus model systems that can parse the functions of the BBB are highly desirable. In this study, we sought to define the transcriptome of the adult Drosophila melanogaster BBB by isolating the BBB surface glia with fluorescence activated cell sorting (FACS) and profiling their gene expression with microarrays. By comparing the transcriptome of these surface glia to that of all brain glia, brain neurons, and whole brains, we present a catalog of transcripts that are selectively enriched at the Drosophila BBB. We found that the fly surface glia show high expression of many ATP-binding cassette (ABC) and solute carrier (SLC) transporters, cell adhesion molecules, metabolic enzymes, signaling molecules, and components of xenobiotic metabolism pathways. Using gene sequence-based alignments, we compare the Drosophila and Murine BBB transcriptomes and discover many shared chemoprotective and small molecule control pathways, thus affirming the relevance of invertebrate models for studying evolutionary conserved BBB properties. The Drosophila BBB transcriptome is valuable to vertebrate and insect biologists alike as a resource for studying proteins underlying diffusion barrier development and maintenance, glial biology, and regulation of drug transport at tissue barriers.

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Section: Resultsmentioning

confidence: 99%

The Drosophila surface glia transcriptome: evolutionary conserved blood-brain barrier processes

et al. 2014

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“…Within the plasma, concentrations of cysteine (10–20 μM) are approximately 10 fold lower than the oxidized form cystine (100–200 μM) [40]. Using a mouse brain endothelial cell line Hosoya et al determined that cystine is transported into brain endothelial cells through the Xc − transporter [48].…”

Section: Glutathione Transport Across the Blood Brain Barriermentioning

confidence: 99%

Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

2012

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Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated.

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“…System x c − was first described by Bannai and Kitamura as a sodium-independent amino acid transport system with a very narrow natural substrate binding profile (6,7), especially when compared with other known transporters (8). This cystine/glutamate transporter is a dimeric cell surface transporter that consists of a heavy chain subunit (4F2hc) for membrane trafficking and xCT, the smaller subunit that imparts substrate specificity.…”

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confidence: 99%

Functional Imaging of Oxidative Stress with a Novel PET Imaging Agent, ¹⁸F-5-Fluoro-l-Aminosuberic Acid

et al. 2014

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Glutathione is the predominant endogenous cellular antioxidant, playing a critical role in the cellular defensive response to oxidative stress by neutralizing free radicals and reactive oxygen species. With cysteine as the rate-limiting substrate in glutathione biosynthesis, the cystine/glutamate transporter (system xc−) represents a potentially attractive PET biomarker to enable in vivo quantification of xc− activity in response to oxidative stress associated with disease. We have developed a system xc− substrate that incorporates characteristics of both natural substrates, l-cystine and l-glutamate (l-Glu). l-aminosuberic acid (l-ASu) has been identified as a more efficient system xc− substrate than l-Glu, leading to an assessment of a series of anionic amino acids as prospective PET tracers. Herein, we report the synthesis and in vitro and in vivo validation of a lead candidate, 18F-5-fluoro-aminosuberic acid (18F-FASu), as a PET tracer for functional imaging of a cellular response to oxidative stress with remarkable tumor uptake and retention. Methods 18F-FASu was identified as a potential PET tracer based on an in vitro screening of compounds similar to l-cystine and l-Glu. Affinity toward system xc− was determined via in vitro uptake and inhibition studies using oxidative stress–induced EL4 and SKOV-3 cells. In vivo biodistribution and PET imaging studies were performed in mice bearing xenograft tumors (EL4 and SKOV-3). Results In vitro assay results determined that l-ASu inhibited system xc− as well as or better than l-Glu. The direct comparison of uptake of tritiated compounds demonstrated more efficient system xc− uptake of l-ASu than l-Glu. Radiosynthesis of 18F-FASu allowed the validation of uptake for the fluorine-bearing derivative in vitro. Evaluation in vivo demonstrated primarily renal clearance and uptake of approximately 8 percentage injected dose per gram in SKOV-3 tumors, with tumor-to-blood and tumor-to-muscle ratios of approximately 12 and approximately 28, respectively. 18F-FASu uptake was approximately 5 times greater than 18F-FDG uptake in SKOV-3 tumors. Dynamic PET imaging demonstrated uptake in EL4 tumor xenografts of approximately 6 percentage injected dose per gram and good tumor retention for at least 2 h after injection. Conclusion 18F-FASu is a potentially useful metabolic tracer for PET imaging of a functional cellular response to oxidative stress. 18F-FASu may provide more sensitive detection than 18F-FDG in certain tumors.

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The role of amino acid transporters in GSH synthesis in the blood–brain barrier and central nervous system

Cited by 44 publications

References 191 publications

The Drosophila surface glia transcriptome: evolutionary conserved blood-brain barrier processes

The Drosophila surface glia transcriptome: evolutionary conserved blood-brain barrier processes

Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

Functional Imaging of Oxidative Stress with a Novel PET Imaging Agent, ¹⁸F-5-Fluoro-l-Aminosuberic Acid

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The role of amino acid transporters in GSH synthesis in the blood–brain barrier and central nervous system

Cited by 44 publications

References 191 publications

The Drosophila surface glia transcriptome: evolutionary conserved blood-brain barrier processes

The Drosophila surface glia transcriptome: evolutionary conserved blood-brain barrier processes

Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

Functional Imaging of Oxidative Stress with a Novel PET Imaging Agent, 18F-5-Fluoro-l-Aminosuberic Acid

Contact Info

Product

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Functional Imaging of Oxidative Stress with a Novel PET Imaging Agent, ¹⁸F-5-Fluoro-l-Aminosuberic Acid