FIGURE 8.

Scheme summarizing the proposed mechanisms underlying neuroprotection of GluR5-containing kainate receptor activation against ischemic brain injury. Ischemia-reperfusion induces entry of excessive Na⁺ and Ca²⁺ ions through NMDA receptors. Activated Src phosphorylates NMDA receptors, which is mediated by PSD-95. The results enhance the NMDA receptor function and further promote the influx of Ca²⁺. The positive feedback mechanism induces the delayed neuronal death. Our present results suggest that activation of GluR5-containing KA receptors induces GABA release from the synaptic terminal of interneurons, which is Ca²⁺-dependent. Released GABA activates postsynaptic GABA_A receptors. Then the influx of Cl^- ions through the GABA_A receptors can counter postsynaptic membrane depolarization and limit calcium entry and then suppress Src activation. Then the interactions among Src, PSD-95, and NR2A, decrease the activity of NMDA channels.