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The cystine/glutamate antiporter system xc- in health and disease: from molecular mechanisms to novel therapeutic opportunities Vrije Universiteit Brussel

Jan Lewerenz, Sandra Hewett, Ying Huang, Maria Lambros, Peter Gout, Peter Kalivas, Ann Massie, Ilse Smolders, Axel Methner, Mathias Pergande, et al.
The antiporter system xc- 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 ...

System xc- as a possible novel target for the treatment of limbic epilepsy and Parkinson's disease Vrije Universiteit Brussel

Joeri Van Liefferinge, Eduard Mihai Bentea, Ellen Merckx, Shiro Bannai, Hideyo Sato
Malfunctioning of system xc-, responsible for exchanging intracellular glutamate for extracellular cystine, can cause oxidative stress as well as excitotoxicity, important phenomenons in the pathogenesis of Parkinson's disease, epilepsy and many other neurological disorders. We observed increased expression levels of xCT, the specific subunit of system xc-, in brain samples of rodent models for several neurological disorders. Therefore, we used ...

Loss of system xc- does not induce oxidative stress but decreases extracellular glutamate in hippocampus and influences spatial working memory and limbic seizure susceptibility Vrije Universiteit Brussel

Anneleen Schallier, Ellen Loyens, Ruani Fernando, H Miyashita, Joeri Van Liefferinge, Katia Vermoesen, Shiro Bannai
System xc- exchanges intracellular glutamate (Glu) for extracellular cystine, giving it a role in intracellular glutathione synthesis and non-vesicular Glu release. We report that mice lacking the specific subunit of system xc- (xCT-/-) do not have lower hippocampal glutathione content or increased oxidative stress, nor exacerbated spatial reference memory deficits with ageing, indicating that loss of system xc- does not induce oxidative stress ...

System xc- deficient mice show decreased susceptibility for limbic seizures as well as for 6-OHDA-induced neurodegeneration Vrije Universiteit Brussel

Anneleen Schallier, S. Kim, Ruani Fernando, Sho Kobayashi, H Miyashita, Heike Beck, Joeri Van Liefferinge, Ellen Loyens, Katia Vermoesen, Shiro Bannai, et al.
Malfunctioning of system xc-, responsible for exchanging intracellular glutamate for extracellular cystine, can cause oxidative stress as well as excitotoxicity, important phenomenons in the pathogenesis of Parkinson's disease and epilepsy.
We used mice lacking xCT (xCT-/- mice), the specific subunit of system xc-, to study in vivo the effect of system xc- deficiency on striatal and hippocampal glutathione content and extracellular ...

Absence of system xc- in mice decreases anxiety and depressive-like behavior without affecting sensorimotor function or spatial vision Vrije Universiteit Brussel KU Leuven

Eduard Mihai Bentea, Thomas Demuyser, Joeri Van Liefferinge, Giulia Albertini, Lauren Deneyer, Julie Nys, Ellen Merckx, Yvette Michotte, Lutgarde Arckens

There is considerable preclinical and clinical evidence indicating that abnormal changes in glutamatergic signaling underlie the development of mood disorders. Astrocytic glutamate dysfunction, in particular, has been recently linked with the pathogenesis and treatment of mood disorders, including anxiety and depression. System xc- is a glial cystine/glutamate antiporter that is responsible for nonvesicular glutamate release in various ...

Slc7a11 (xCT) protein expression is not altered in the depressed brain and system xc- deficiency does not affect depression-associated behaviour in the corticosterone mouse model Vrije Universiteit Brussel

Thomas Demuyser, Lauren Deneyer, Eduard Mihai Bentea, Giulia Albertini, Teresa Femenía, Laura Walrave, Hideyo SATO, Niels C Danbolt, Dimitri De Bundel, Alex Michotte, et al.

OBJECTIVES: The cystine/glutamate antiporter (system xc-) is believed to contribute to nonvesicular glutamate release from glial cells in various brain areas. Although recent investigations implicate system xc- in mood disorders, unambiguous evidence has not yet been established. Therefore, we evaluated the possible role of system xc- in the depressive state.

METHODS: We conducted a protein expression analysis of the specific subunit ...

Structural investigation of human cystine/glutamate antiporter system xc− (Sxc−) using homology modeling and molecular dynamics Vrije Universiteit Brussel

Dieu Hang Tran, Minh Hung Huynh, Pauline Beckers, Nathalie Desmet, Mohamed Lamrani, Ann Massie, Emmanuel Hermans, Kenno Vanommeslaeghe

The cystine/glutamate antiporter system xc− (Sxc−) belongs to the SLC7 family of plasma membrane transporters. It exports intracellular glutamate along the latter’s concentration gradient as a driving force for cellular uptake of cystine. Once imported, cystine is mainly used for the production of glutathione, a tripeptide thiol crucial in maintenance of redox homeostasis and protection of cells against oxidative stress. Overexpression of ...

Phosphoinositide 3-Kinases Upregulate System xc− via Eukaryotic Initiation Factor 2α and Activating Transcription Factor 4 – A Pathway Active in Glioblastomas and Epilepsy Vrije Universiteit Brussel

Jan Lewerenz, Paul Baxter, Rebecca Kassubek, Kristof Albrecht, Joeri Van Liefferinge, Mike-Andrew Westhoff, Marc-Eric Halatsch, Georg Karpel-Massler, Paul J. Meakin, John D. Hayes, et al.
Aims: Phosphoinositide 3-kinases (PI3Ks) relay growth factor signaling and mediate cytoprotection and cell growth. The cystine/glutamate antiporter system xc - imports cystine while exporting glutamate, thereby promoting glutathione synthesis while increasing extracellular cerebral glutamate. The aim of this study was to analyze the pathway through which growth factor and PI3K signaling induce the cystine/glutamate antiporter system xc - and to ...

Implication of system xc- in neuroinflammation during the onset and maintenance of neuropathic pain Vrije Universiteit Brussel

Pauline Beckers, Ines Belo do Nascimento, Mathilde Charlier, Nathalie Desmet, Ann Massie, Emmanuel Hermans
Background Despite the high prevalence of neuropathic pain, treating this neurological disease remains
challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity
in patient management is largely attributed to an incomplete understanding of the underlying pathological
mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent ...