Abstract:Transport system x c؊ found in plasma membrane of cultured mammalian cells is an exchange agency for anionic amino acids with high specificity for anionic form of cystine and glutamate. We have isolated cDNA encoding the transporter for system x c Ϫ from mouse activated macrophages by expression in Xenopus oocytes. The expression of system x c Ϫ activity in oocytes required two cDNA transcripts, and the sequence analysis revealed that one is identical with the heavy chain of 4F2 cell surface antigen (4F2hc) an… Show more
“…Moreover, amino acids and amino acid transporters play important roles other than in energy metabolism, such as in macromolecular synthesis, mTOR activation, and ROS homeostasis beyond energy metabolism [49]. There are approximately fifty different types of amino acid transporters, but only LAT1 [50], LAT3 [51], ASCT2 [52], ATB 0, + [53] and xCT [54] have been reported to be expressed at high levels on the surface of cancer cells. Recently, there have been numerous reports in cancer cells related to glutamine transport via ASCT2 and LAT1 [55][56][57].…”
Results and Conclusion: [ 14 C]MeAIB uptake occurred principally via a Na + -dependent A type mechanism whereas [ 3 H]MET uptake, which occurred predominantly via a Na + -independent L type mechanism although other transporters were also utilized depending on cell type. There was no correlation between [ 3 H]MET uptake and total system L amino acid transporter (LAT) expression. In contrast, [ 14 C]MeAIB uptake strongly correlated with total system A amino acid transporter (SNAT) expression and proliferative activity in this preliminary study using four human carcinoma cell lines. Carcinoma proliferative activity also correlated with total SNAT expression.
“…Moreover, amino acids and amino acid transporters play important roles other than in energy metabolism, such as in macromolecular synthesis, mTOR activation, and ROS homeostasis beyond energy metabolism [49]. There are approximately fifty different types of amino acid transporters, but only LAT1 [50], LAT3 [51], ASCT2 [52], ATB 0, + [53] and xCT [54] have been reported to be expressed at high levels on the surface of cancer cells. Recently, there have been numerous reports in cancer cells related to glutamine transport via ASCT2 and LAT1 [55][56][57].…”
Results and Conclusion: [ 14 C]MeAIB uptake occurred principally via a Na + -dependent A type mechanism whereas [ 3 H]MET uptake, which occurred predominantly via a Na + -independent L type mechanism although other transporters were also utilized depending on cell type. There was no correlation between [ 3 H]MET uptake and total system L amino acid transporter (LAT) expression. In contrast, [ 14 C]MeAIB uptake strongly correlated with total system A amino acid transporter (SNAT) expression and proliferative activity in this preliminary study using four human carcinoma cell lines. Carcinoma proliferative activity also correlated with total SNAT expression.
“…Cystine uptake in many types of cells is mediated by system X c -, a Na ? -independent cystine/ glutamate antiporter [78]. System X c -is a member of the disulfide-linked heteromeric amino acid transporter family and consists of a light chain (xCT) that confers substrate specificity and a heavy chain (4F2hc) that is shared among a number of different amino acid transporters.…”
Multiple factors have been implicated in the age-related declines in brain function. Thus, it is unlikely that modulating only a single factor will be effective at slowing this decline. A better approach is to identify small molecules that have multiple biological activities relevant to the maintenance of brain function. Over the last few years, we have identified an orally active, novel neuroprotective and cognition-enhancing molecule, the flavonoid fisetin. Fisetin not only has direct antioxidant activity but it can also increase the intracellular levels of glutathione, the major intracellular antioxidant. Fisetin can also maintain mitochondrial function in the presence of oxidative stress. In addition, it has anti-inflammatory activity against microglial cells and inhibits the activity of 5-lipoxygenase, thereby reducing the production of lipid peroxides and their pro-inflammatory by-products. This wide range of actions suggests that fisetin has the ability to reduce the age-related decline in brain function.
“…This may reflect blunted cystine-glutamate exchange because cystine uptake into the cell represents the rate-limiting step in glutathione synthesis (Bannai, 1984;Meister, 1991;Sies, 1999). Alternatively, this could cause blunted cystine-glutamate exchange because extracellular glutathione metabolism serves as a reservoir for cystine that is critical in maintaining cystine-glutamate exchange (Deneke and Fanburg, 1989;Sato et al, 1999;Sies, 1999;Kim et al, 2001;Shih et al, 2006). Regardless, either would diminish glutamate release from cystine-glutamate exchange.…”
Section: Cystine-glutamate Exchange and Schizophreniamentioning
Altered glutamate signaling contributes to a myriad of neural disorders, including schizophrenia. While synaptic levels are intensely studied, nonvesicular release mechanisms, including cystine-glutamate exchange, maintain high steady-state glutamate levels in the extrasynaptic space. The existence of extrasynaptic receptors, including metabotropic group II glutamate receptors (mGluR), pose nonvesicular release mechanisms as unrecognized targets capable of contributing to pathological glutamate signaling. We tested the hypothesis that activation of cystine-glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt psychotomimetic effects in the rodent phencyclidine (PCP) model of schizophrenia. First, we demonstrate that PCP elevates extracellular glutamate in the prefrontal cortex, an effect that is blocked by N-acetylcysteine pretreatment. To determine the relevance of the above finding, we assessed social interaction and found that N-acetylcysteine reverses social withdrawal produced by repeated PCP. In a separate paradigm, acute PCP resulted in working memory deficits assessed using a discrete trial t-maze task, and this effect was also reversed by Nacetylcysteine pretreatment. The capacity of N-acetylcysteine to restore working memory was blocked by infusion of the cystineglutamate antiporter inhibitor (S)-4-carboxyphenylglycine into the prefrontal cortex or systemic administration of the group II mGluR antagonist LY341495 indicating that the effects of N-acetylcysteine requires cystine-glutamate exchange and group II mGluR activation. Finally, protein levels from postmortem tissue obtained from schizophrenic patients revealed significant changes in the level of xCT, the active subunit for cystine-glutamate exchange, in the dorsolateral prefrontal cortex. These data advance cystine-glutamate antiporters as novel targets capable of reversing the psychotomimetic effects of PCP.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.