Fig. 5

DAPK1 dysregulation leads to neuronal cell death through multiple pathways. a DAPK1 interacts with the GluN2B subunit of extrasynaptic NMDAR and phosphorylates the Ser1303 of GluN2B, thereby elevating the channel conductance of NMDAR toward Ca²⁺. Ultimately, neurons experience extensive excitotoxicity and undergo apoptosis due to Ca²⁺ overload. b DAPK1 directly phosphorylates the Ser23 of p53. Phosphorylated p53 enters cell nucleus to promote the transcription of pro-apoptotic genes such as Bax and Puma, leading to neuronal cell death in ischemic stroke. Besides, it can anchor to mitochondrial membranes and disrupt membrane integrity by interacting with the cyclophilin D (Cyp D), causing the release of cytochrome c and the generation of cle-caspase-3. c DAPK1 upregulation causes the phosphorylation of the Ser350 residue of NDRG2, resulting in the activation of caspase-3-dependent neuronal cell death