Displacement of α-actinin from the NMDA receptor NR1 C0 domain by Ca²⁺/calmodulin promotes CaMKII binding

Ca²⁺ influx through the N-methyl-D-aspartate (NMDA)-type glutamate receptor triggers activation and postsynaptic accumulation of Ca ²⁺/calmodulin-dependent kinase II (CaMKII). CaMKII, calmodulin, and α-actinin directly bind to the short membrane proximal C0 domain of the C-terminal region of the NMDA receptor NR1 subunit. In a negative feedback loop, calmodulin mediates Ca²⁺-dependent inactivation of the NMDA receptor by displacing α-actinin from NR1 C0 upon Ca²⁺ influx. We show that Ca²⁺-depleted calmodulin and α-actinin simultaneously bind to NR1 C0. Upon addition of Ca²⁺, calmodulin dislodges α-actinin. Either the N- or C-terminal half of calmodulin is sufficient for Ca²⁺-induced displacement of α-actinin. Whereas α-actinin directly antagonizes CaMKII binding to NR1 C0, the addition of Ca²⁺/calmodulin shifts binding of NR1 C0 toward CaMKII by displacing α-actinin. Displacement of α-actinin results in the simultaneous binding of calmodulin and CaMKII to NR1 C0. Our results reveal an intricate mechanism whereby Ca²⁺ functions to govern the complex interactions between the two most prevalent signaling molecules in synaptic plasticity, the NMDA receptor and CaMKII.