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 site， due to its high net positive charge. Thus， GluN2B-driven excitotoxic signaling can proceed independently of Dapk1 or altered Ser-1303 phosphorylation.