Protein Kinase C Activation Modulates α-Calmodulin Kinase II Binding to NR2A Subunit of N-Methyl-D-Aspartate 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 α-calmodulin kinase II (αCaMKII) 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 αCaMKII binding, and we identify, by site directed mutagenesis, PKC-dependent phosphorylation of NR2A-(Ser1416) as a key mechanism in inhibiting αCaMKII binding and promoting dissociation of αCaMKII·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 αCa-MKII binding to NMDA receptor complex. Thus, our data provide clues on understanding the molecular basis of a direct cross-talk between αCaMKII and PKC pathways in the postsynaptic compartment.