| First Author | McQueen J | Year | 2017 |
| Journal | Elife | Volume | 6 |
| PubMed ID | 28731405 | Mgi Jnum | J:255304 |
| Mgi Id | MGI:6114274 | Doi | 10.7554/eLife.17161 |
| Citation | McQueen J, et al. (2017) Pro-death NMDA receptor signaling is promoted by the GluN2B C-terminus independently of Dapk1. Elife 6:e17161 |
| abstractText | Aberrant NMDA receptor (NMDAR) activity contributes to several neurological disorders, but direct antagonism is poorly tolerated therapeutically. The GluN2B cytoplasmic C-terminal domain (CTD) represents an alternative therapeutic target since it potentiates excitotoxic signaling. The key GluN2B CTD-centred event in excitotoxicity is proposed to involve its phosphorylation at Ser-1303 by Dapk1, that is blocked by a neuroprotective cell-permeable peptide mimetic of the region. Contrary to this model, we find that excitotoxicity can proceed without increased Ser-1303 phosphorylation, and is unaffected by Dapk1 deficiency in vitro or following ischemia in vivo. Pharmacological analysis of the aforementioned neuroprotective peptide revealed that it acts in a sequence-independent manner as an open-channel NMDAR antagonist at or near the Mg(2+) site, due to its high net positive charge. Thus, GluN2B-driven excitotoxic signaling can proceed independently of Dapk1 or altered Ser-1303 phosphorylation. |
