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Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage
- Source :
- Journal of Clinical Investigation. 124:3645-3655
- Publication Year :
- 2014
- Publisher :
- American Society for Clinical Investigation, 2014.
-
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.
- Subjects :
- Amino Acid Transport System y+
Vesicular Glutamate Transport Proteins
Antiporter
Glycine
Glutamic Acid
Glutamate Plasma Membrane Transport Proteins
Biology
Benzoates
Receptors, N-Methyl-D-Aspartate
Brain Ischemia
Rats, Sprague-Dawley
Mice
Glutamate homeostasis
Animals
Mice, Knockout
Mice, Inbred C3H
Cell Death
Pyramidal Cells
Glutamate receptor
General Medicine
Glutamic acid
Rats
Cell biology
nervous system
Biochemistry
Metabotropic glutamate receptor
Commentary
NMDA receptor
Ion Channel Gating
Subjects
Details
- ISSN :
- 00219738
- Volume :
- 124
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....9a041060cf55aa6d0c6d3b6a69f5f330
- Full Text :
- https://doi.org/10.1172/jci71886