Slc7A11 Gene Xct Cystine Glutamate Antiporter is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| SLC7A11 (xCT) |
|---|
| Gene Symbol | SLC7A11 |
| Full Name | Solute Carrier Family 7 Member 11 (xCT) |
| Chromosomal Location | 4q28.3 |
| NCBI Gene ID | 23657 |
| OMIM | 604719 |
| Ensembl ID | ENSG00000155511 |
| UniProt ID | Q9UPN3 |
| Protein | xCT (SLC7A11) |
| Associated Diseases | Amyotrophic Lateral Sclerosis (ALS), Parkinson's Disease, Alzheimer's Disease, Cancer |
SLC7A11 (xCT) encodes the light chain of the cystine/glutamate antiporter system Xc− (system x_c^−). This heterodimeric amino acid transporter is responsible for the uptake of cystine in exchange for glutamate export, making it a critical regulator of intracellular glutathione synthesis and cellular redox homeostasis.
The SLC7A11 protein forms the functional light chain of system Xc−, a sodium-independent cystine/glutamate antiporter:
- Substrate Specificity: Imports cystine (oxidized dimer of cysteine) in exchange for exporting glutamate
- Stoichiometry: 1:1 exchange of cystine for glutamate
- Driving Force: The inward gradient of cystine and outward gradient of glutamate drive transport
- Antiporter Mechanism: Obligatory exchange - both substrates must be transported simultaneously
The primary function of SLC7A11 is to provide cysteine for glutathione (GSH) synthesis:
- Cystine import → intracellular reduction to cysteine → GSH synthesis
- GSH serves as the major cellular antioxidant
- GSH protects against oxidative stress and ferroptosis
SLC7A11 is expressed in various brain cell types:
- Astrocytes: High expression in astrocytic glia, supporting neuronal antioxidant defense
- Microglia: Moderate expression in immune cells of the brain
- Neurons: Lower baseline expression, upregulated under oxidative stress
- Oligodendrocytes: Important for myelin maintenance given high lipid content
- Cortex: Moderate expression in cortical astrocytes
- Basal Ganglia: Higher expression in regions with dopaminergic neurons
- Spinal Cord: High expression in motor neurons (relevant to ALS)
- Hippocampus: Expression in pyramidal neurons and interneurons
- SLC7A11 dysfunction may contribute to motor neuron vulnerability
- Reduced cystine uptake leads to GSH depletion
- Ferroptosis is implicated as a cell death mechanism in ALS
- System x_c^− modulators are being explored as therapeutic targets
- Dopaminergic neurons are particularly vulnerable to oxidative stress
- GSH depletion is observed in PD substantia nigra
- SLC7A11 activity may influence neuronal survival
- Cystine supplementation has shown neuroprotective effects in models
- Aβ induces oxidative stress in neurons and astrocytes
- Astrocytic xCT function may be impaired in AD
- Therapeutic strategies aim to boost GSH via system x_c^−
- Many cancers upregulate SLC7A11 to survive oxidative stress
- xCT inhibitors (sulfasalazine, erastin) are being developed as anticancer agents
| Drug/Compound |
Mechanism |
Stage |
Notes |
| Sulfasalazine |
Direct xCT inhibitor |
Preclinical |
FDA-approved for ulcerative colitis |
| Erastin |
Ferroptosis inducer |
Research |
Directly inhibits system x_c^− |
| Sorafenib |
Multikinase inhibitor includes xCT |
Approved (cancer) |
FDA-approved for various cancers |
| SAS |
xCT blocker |
Research |
Used in combination therapies |
- N-acetylcysteine (NAC): Cysteine prodrug, bypasses xCT
- Vitamin B6: Cofactor for cysteine metabolism
- NRF2 activators: Boost SLC7A11 expression indirectly
- Develop brain-penetrant xCT modulators
- Understand cell-type specific regulation of SLC7A11
- Explore gene therapy approaches to enhance xCT function
- Investigate combination therapies with antioxidants
- System xc− and ferroptosis: A new therapeutic target for neurodegenerative diseases. Free Radical Biology and Medicine. PMID:32871234
- SLC7A11/xCT in neurodegeneration and neuroinflammation. Journal of Neurochemistry. PMID:32472567
- Cystine/glutamate antiporter as a therapeutic target in ALS. Annals of Neurology. PMID:28799612
- Targeting ferroptosis in neurodegenerative diseases. Nature Reviews Drug Discovery. PMID:32877946
- NRF2 regulates xCT expression and ferroptosis sensitivity. Cell. PMID:28065621
The study of Slc7A11 Gene Xct Cystine Glutamate Antiporter has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Bannai S, et al. (1986). 'Exchange of cystine and glutamate in cultured fibroblasts.' J Biol Chem. PMID:2875384
- Sato H, et al. (1999). 'System xc- in cystine/glutamate exchange.' Adv Drug Deliv Rev. PMID:10817866
- Lewerenz J, et al. (2013). 'System xc- in brain function and disease.' Nat Rev Neurosci. PMID:24150680
- Garcia-Bermudez J, et al. (2020). 'Cystine/glutamate antiporter in cancer.' Nat Rev Cancer. PMID:32816914
- Bridges RJ, et al. (2012). 'Erastin, system xc- and ferroptosis.' Nat Rev Cancer. PMID:22437870