Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage
J. Clin. Invest.. 2014-07-18; 124(8): 3645-3655
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1. J Clin Invest. 2014 Aug;124(8):3645-55. doi: 10.1172/JCI71886. Epub 2014 Jul 18.
Extrasynaptic glutamate release through cystine/glutamate antiporter contributes
to ischemic damage.
Soria FN, Pérez-Samartín A, Martin A, Gona KB, Llop J, Szczupak B, Chara JC,
Matute C, Domercq M.
J Clin Invest. 2014 Aug;124(8):3279-81.
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.
PMID: 25036707 [Indexed for MEDLINE]