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 N R2 subunits of the NMDA receptor complex. The nature and mechanisms of targ eting to the NMDA receptor subunits are, however, not completely understood . Here we report that the C-terminal NR2A(S1389-V1464) sequence was suffici ent to guarantee the association of both native and recombinant alpha CaMKI I and PSD-95. PSD-95(54-256) was able to compete with the binding of both n ative and recombinant alpha CaMKII to the NR2A C-tail. Accordingly, alpha C aMKII(1-325) competes with both the native PSD-95 and the native kinase its elf for the binding to NR2A. In addition, Ser/Ala1289 and Ser/Asp1289 point mutations on the unique CaMKII phosphosite of NR2A did not significantly i nfluence 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 fro m the NR2A C-tail was significantly modulated by activation of NMDA recepto r achieved by either pharmacological tools or long-term potentiation induct ion, underlining the importance of dynamic and reciprocal interactions of N MDA receptor, alpha CaMKII, and PSD-95 in hippocampal synaptic plasticity.