Hippocampal synaptic plasticity involves competition between Ca2+/calmodulin-dependent protein kinase II and postsynaptic density 95 for binding to the NR2A subunit of the NMDA receptor

NMDA receptor, Ca2+/calmodulin-dependent protein kinase II (alpha CaMKII), and postsynaptic density 95 (PSD-95) are three major components of the PSD fraction. Both alpha CaMKII and PSD-95 have been shown previously to bind NR2 subunits of the NMDA receptor complex. The nature and mechanisms of targeting to the NMDA receptor subunits are, however, not completely understood. Here we report that the C-terminal NR2A(S1389-V1464) sequence was sufficient to guarantee the association of both native and recombinant alpha CaMKII and PSD-95. PSD-95(54-256) was able to compete with the binding of both native and recombinant alpha CaMKII to the NR2A C-tail. Accordingly, alpha CaMKII(1-325) competes with both the native PSD-95 and the native kinase itself for the binding to NR2A. In addition, Ser/Ala1289 and Ser/Asp1289 point mutations on the unique CaMKII phosphosite of NR2A did not significantly influence the binding of native alpha CaMKII and PSD-95 to the NR2A C-tail. Finally, the association-dissociation of alpha CaMKII and PSD-95 to and from the NR2A C-tail was significantly modulated by activation of NMDA receptor achieved by either pharmacological tools or long-term potentiation induction, underlining the importance of dynamic and reciprocal interactions of NMDA receptor, alpha CaMKII, and PSD-95 in hippocampal synaptic plasticity.