title: Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage.
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.
authors.forename: Federico N
authors.initials: FN
authors.lastname: Soria
authors.forename: Alberto
authors.initials: A
authors.lastname: Pérez-Samartín
authors.forename: Abraham
authors.initials: A
authors.lastname: Martin
authors.forename: Kiran Babu
authors.initials: KB
authors.lastname: Gona
authors.forename: Jordi
authors.initials: J
authors.lastname: Llop
authors.forename: Boguslaw
authors.initials: B
authors.lastname: Szczupak
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Chara
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
authors.forename: María
authors.initials: M
authors.lastname: Domercq
mesh_terms: D027182:Amino Acid Transport System y+ / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002545:Brain Ischemia / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death; D050491:Glutamate Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D015640:Ion Channel Gating / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D050496:Vesicular Glutamate Transport Proteins / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D027182:Amino Acid Transport System y+; D001565:Benzoates; D050491:Glutamate Plasma Membrane Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C492255:Slc7a11 protein, mouse; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid; C079693:4-carboxyphenylglycine; D005998:Glycine