Recent studies have shown that GluR6 is involved in the modulation of neuronal cell death. It has been shown that PKA can phosphorylate recombinant GluR6 homomeric receptors and that this phosphorylation of GluR6 was suggested to underlie an enhancement of whole-cell current responses. Here, we try to find out whether brain ischemia and reperfusion could induce any change in the serine phosphorylation of GluR6. Our results showed that the serine phosphorylation of GluR6 increased in hippocampus during brain ischemia and early reperfusion period. Then, we used several drugs to investigate the mechanism of modulating the serine phosphorylation of GluR6. KT5720, a specific cell-permeable inhibitor of protein kinase A (PKA), had no effect on the increase in serine phosphorylation of GluR6 induced by brain ischemia or reperfusion. On the other hand, KN-62, a selective inhibitor of rat brain Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), diminished the increase in serine phosphorylation of GluR6. Moreover, our results showed that either MK801 (a NMDA receptor antagonist) or Nifedipine (a L-type Ca2+ channel (L-VGCC) blocker) decreased the increase in serine phosphorylation. In conclusion, our results suggest that CaMKII, activated through NMDA receptors and L-VGCCs, mediated the serine phosphorylation of GluR6 during brain ischemia and early reperfusion period.