Transduced PDZ1 domain of PSD-95 decreases Src phosphorylation and increases nNOS (Ser847) phosphorylation contributing to neuroprotection after cerebral ischemia

Over-activation of NMDA receptor has been widely believed to be the main signal resulting in ischemic cell injury. We recently reported that the triplicate complex NR2A–PSD-95–Src is a signaling module to facilitate NMDA receptor over-activation. In addition, over-activation of NMDA receptor can activate another signaling molecule nNOS, which is also mediated by PSD-95 after cerebral ischemia. Here, we examined whether overexpression of the PDZ1 domain of PSD-95 could disrupt the functional interaction between NMDA receptor and PSD-95 in rat hippocampal CA1 region, and whether or not it could exert a neuroprotective effect against cerebral ischemia. Our results showed that overexpression of PDZ1 domain not only decreased the assembly of NR2A–PSD-95–Src signaling module and the auto-phosphorylation of Src, which mediates NMDA receptor phosphorylation, but also enhanced nNOS (Ser847) phosphorylation. Most importantly, overexpression of PDZ1 domain protected rat hippocampal CA1 neurons against cerebral ischemia injury. These results suggest that overexpression of the PDZ1 domain can perturb the binding of PSD-95 to NMDA receptor, suppress the activity of both NMDA receptor and nNOS, and thus have a neuroprotective effect.