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.
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