| First Author | Minnella AM | Year | 2018 |
| Journal | Sci Rep | Volume | 8 |
| Issue | 1 | Pages | 17522 |
| PubMed ID | 30504838 | Mgi Jnum | J:268460 |
| Mgi Id | MGI:6270923 | Doi | 10.1038/s41598-018-35725-5 |
| Citation | Minnella AM, et al. (2018) Excitotoxic superoxide production and neuronal death require both ionotropic and non-ionotropic NMDA receptor signaling. Sci Rep 8(1):17522 |
| abstractText | NMDA-type glutamate receptors (NMDAR) trigger superoxide production by neuronal NADPH oxidase-2 (NOX2), which if sustained leads to cell death. This process involves Ca(2+) influx through NMDAR channels. By contrast, comparable Ca(2+) influx by other routes does not induce NOX2 activation or cell death. This contrast has been attributed to site-specific effects of Ca(2+) 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 Ca(2+) influx through NMDAR channels but not NMDA binding. NMDA-induced superoxide formation was prevented by the channel blockers, restored by concurrent Ca(2+) influx through ionomycin or voltage-gated calcium channels, and not induced by the Ca(2+) 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 Ca(2+) influx. These findings identify a non-ionotropic signaling pathway that links NMDAR to NOX2 activation through the C-terminus domain of GluN2B. |
