ArticleThe Journal of clinical investigation2014
Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage.
Article in The Journal of clinical investigation, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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Who cites it
82 citing papers in PubMed.
- ASIC1a as an integrating node in ischemic neurotoxicity: crosstalk with NMDAR and TRPM signaling.Pflugers Archiv : European journal of physiology · 2026Review
- Ubiquitination-dependent regulation of ferroptosis in ischemic heart and brain.Redox biology · 2026Review
- Oxytocin-mediated neuroprotection in ischemic stroke: molecular mechanisms, therapeutic potential and clinical translational prospects.Metabolic brain disease · 2025Review
- Plasma Cystine as a Marker of Acute Stroke Severity.Diagnostics (Basel, Switzerland) · 2025Article
- ARIP1 Deficiency Facilitates the Inhibition of Neuronal Ferroptosis in Cerebral Ischemia by Activin A Through SMAD3 and p38 MAPK Signaling.CNS neuroscience & therapeutics · 2025Article
- An Integrated Network Pharmacology, Molecular Docking, Molecular Dynamics Simulation, and Experimental Validation Study to Investigate the Potential Mechanism of Isoliquiritigenin in the Treatment of Ischemic Stroke.Current issues in molecular biology · 2025Article
- The Crucial Interplay Between the Lungs, Brain, and Heart to Understand Epilepsy-Linked SUDEP: A Literature Review.Brain sciences · 2025Review
- How to Pick a Neuroprotective Drug in Stroke Without Losing Your Mind?Life (Basel, Switzerland) · 2025Review
- Neuropsychiatric Manifestations of COVID-19 Disease and Post COVID Syndrome: The Role of N-acetylcysteine and Acetyl-L-carnitine.Current neuropharmacology · 2025Review
- Contrasting patterns of extrasynaptic NMDAR-GluN2B expression in macaque subgenual cingulate and dorsolateral prefrontal cortices.Frontiers in neuroanatomy · 2025Article
- Anesthesia-Induced Ferroptosis: Bidirectional Regulation and Molecular Mechanisms in Cardio-Cerebral Injury.Journal of inflammation research · 2025Review
- System Xc-pathway as a potential regulatory target in neurological disorders.Frontiers in pharmacology · 2025Review
- Article
- Interference with glutamate antiporter system xExperimental physiology · 2024Article
- Excitotoxicity, Oxytosis/Ferroptosis, and Neurodegeneration: Emerging Insights into Mitochondrial Mechanisms.Aging and disease · 2024Review
- Mechanism of ferroptosis regulating ischemic stroke and pharmacologically inhibiting ferroptosis in treatment of ischemic stroke.CNS neuroscience & therapeutics · 2024Review
- Implication of system xJournal of neuroinflammation · 2024Article
- Mitochondrial Calcium Uniporter (MCU) is Involved in an Ischemic Postconditioning Effect Against Ischemic Reperfusion Brain Injury in Mice.Cellular and molecular neurobiology · 2024Article
- Magnetic field in the extreme low frequency band protects neuronal and microglia cells from oxygen-glucose deprivation.Frontiers in cellular neuroscience · 2024Article
- The Disruption of NMDAR/TRPM4 Death Signaling with TwinF Interface Inhibitors: A New Pharmacological Principle for Neuroprotection.Pharmaceuticals (Basel, Switzerland) · 2023Review
22 more citing papers are in PubMed but not listed here.
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9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
During brain ischemia, an excessive release of glutamate triggers neuronal death through the overactivation of NMDA receptors (NMDARs); however, the underlying pathways that alter glutamate homeostasis and whether synaptic or extrasynaptic sites are responsible for excess glutamate remain controversial. Here, we monitored ischemia-gated currents in pyramidal cortical neurons in brain slices from rodents in response to oxygen and glucose deprivation (OGD) as a real-time glutamate sensor to identify the source of glutamate release and determined the extent of neuronal damage. Blockade of excitatory amino acid transporters or vesicular glutamate release did not inhibit ischemia-gated currents or neuronal damage after OGD. In contrast, pharmacological inhibition of the cystine/glutamate antiporter dramatically attenuated ischemia-gated currents and cell death after OGD. Compared with control animals, mice lacking a functional cystine/glutamate antiporter exhibited reduced anoxic depolarization and neuronal death in response to OGD. Furthermore, glutamate released by the cystine/glutamate antiporter activated extrasynaptic, but not synaptic, NMDARs, and blockade of extrasynaptic NMDARs reduced ischemia-gated currents and cell damage after OGD. Finally, PET imaging showed increased cystine/glutamate antiporter function in ischemic rats. Altogether, these data suggest that cystine/glutamate antiporter function is increased in ischemia, contributing to elevated extracellular glutamate concentration, overactivation of extrasynaptic NMDARs, and ischemic neuronal death.
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