Excitotoxic superoxide production and neuronal death require both ionotropic and non-ionotropic NMDA receptor signaling
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Excitotoxic superoxide production and neuronal death require both ionotropic and non-ionotropic NMDA receptor signaling. / Minnella, Angela M; Zhao, Jerry X; Jiang, Xiangning; Jakobsen, Emil; Lu, Fuxin; Wu, Long; El-Benna, Jamel; Gray, John A; Swanson, Raymond A.
In: Scientific Reports, Vol. 8, No. 1, 17522, 30.11.2018.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Excitotoxic superoxide production and neuronal death require both ionotropic and non-ionotropic NMDA receptor signaling
AU - Minnella, Angela M
AU - Zhao, Jerry X
AU - Jiang, Xiangning
AU - Jakobsen, Emil
AU - Lu, Fuxin
AU - Wu, Long
AU - El-Benna, Jamel
AU - Gray, John A
AU - Swanson, Raymond A
PY - 2018/11/30
Y1 - 2018/11/30
N2 - NMDA-type glutamate receptors (NMDAR) trigger superoxide production by neuronal NADPH oxidase-2 (NOX2), which if sustained leads to cell death. This process involves Ca2+ influx through NMDAR channels. By contrast, comparable Ca2+ influx by other routes does not induce NOX2 activation or cell death. This contrast has been attributed to site-specific effects of Ca2+ flux through NMDAR. Here we show instead that it stems from non-ionotropic signaling by NMDAR GluN2B subunits. To evaluate non-ionotropic effects, mouse cortical neurons were treated with NMDA together with 7-chlorokynurenate, L-689,560, or MK-801, which block Ca2+ influx through NMDAR channels but not NMDA binding. NMDA-induced superoxide formation was prevented by the channel blockers, restored by concurrent Ca2+ influx through ionomycin or voltage-gated calcium channels, and not induced by the Ca2+ influx in the absence of NMDAR ligand binding. Neurons expressing either GluN2B subunits or chimeric GluN2A/GluN2B C-terminus subunits exhibited NMDA-induced superoxide production, whereas neurons expressing chimeric GluN2B/GluN2A C-terminus subunits did not. Neuronal NOX2 activation requires phosphoinositide 3-kinase (PI3K), and NMDA binding to NMDAR increased PI3K association with NMDA GluN2B subunits independent of Ca2+ influx. These findings identify a non-ionotropic signaling pathway that links NMDAR to NOX2 activation through the C-terminus domain of GluN2B.
AB - NMDA-type glutamate receptors (NMDAR) trigger superoxide production by neuronal NADPH oxidase-2 (NOX2), which if sustained leads to cell death. This process involves Ca2+ influx through NMDAR channels. By contrast, comparable Ca2+ influx by other routes does not induce NOX2 activation or cell death. This contrast has been attributed to site-specific effects of Ca2+ flux through NMDAR. Here we show instead that it stems from non-ionotropic signaling by NMDAR GluN2B subunits. To evaluate non-ionotropic effects, mouse cortical neurons were treated with NMDA together with 7-chlorokynurenate, L-689,560, or MK-801, which block Ca2+ influx through NMDAR channels but not NMDA binding. NMDA-induced superoxide formation was prevented by the channel blockers, restored by concurrent Ca2+ influx through ionomycin or voltage-gated calcium channels, and not induced by the Ca2+ influx in the absence of NMDAR ligand binding. Neurons expressing either GluN2B subunits or chimeric GluN2A/GluN2B C-terminus subunits exhibited NMDA-induced superoxide production, whereas neurons expressing chimeric GluN2B/GluN2A C-terminus subunits did not. Neuronal NOX2 activation requires phosphoinositide 3-kinase (PI3K), and NMDA binding to NMDAR increased PI3K association with NMDA GluN2B subunits independent of Ca2+ influx. These findings identify a non-ionotropic signaling pathway that links NMDAR to NOX2 activation through the C-terminus domain of GluN2B.
U2 - 10.1038/s41598-018-35725-5
DO - 10.1038/s41598-018-35725-5
M3 - Journal article
C2 - 30504838
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 17522
ER -
ID: 222091911