Figure 2. Non-ionotropic NMDAR signaling in neuronal dysfunction and disease.

(A) Non-ionotropic NMDAR signaling contributes to excitotoxicity. Ligand binding to the NMDAR drives opening of intracellular calcium stores and inhibition of eEF-2 and protein synthesis. Glutamate and co-agonist binding to the NMDAR leads to Src kinase activation and the opening of Pannexin-1 channels and Ca²⁺ influx, which drives the mitochondrial dysfunction, contributing to excitotoxicity. Ligand binding to GluN2B-containing NMDARs increases binding of p85 to GluN2B C-tail, removing the PI3K regulatory domain so PI3K can activate NOX2 and superoxide production that results in excitotoxicity. (B) Synaptic dysfunction associated with Alzheimer’s disease can be mediated through non-ionotropic NMDAR signaling, β-amyloid acting via GluN2B subunit-containing NMDAR complexes results in activation of p38 MAPK and drives LTD and dendritic spine elimination.