Protein kinase c activation modulates α-calmodulin kinase II bindiag to NR2A subunit of N-methyl-D-aspaatttt receptor complex

The N-methyl-D-aspartate (NMDA) receptor subunits NR2 possess extended intracellular C-terminal domains by which they can directly interact with a large number of postsynaptic density (PSD) proteins involved in synaptic clustering and signaling. We have previously shown that PSD-associated alpha -calmodulin kinase II (alpha CaMKII) binds with high affinity to the C-terminal domain of the NR2A subunit, Here, we show that residues 1412-1419 of the cytosolic tail of NR2A are critical for alpha CaMKII binding, and we identify, by site directed mutagenesis, PKC-dependent phosphorylation of NR2A(Ser(1416)) as a key mechanism in inhibiting alpha CaMKII-binding and promoting dissociation of alpha CaMKII(.)NR2A complex. In addition, we show that stimulation of PKC activity in hippocampal slices either with phorbol esters or with the mGluRs specific agonist trans-1-amino-1,3-cyclopentanedicarboxylic acid (t-ACPD) decreases alpha CaMKII binding to NMDA receptor complex. Thus, our data provide clues on understanding the molecular basis of a direct cross-talk between alpha CaMKII and PKC pathways in the postsynaptic compartment.