Displacement of alpha -Actinin from the NMDA Receptor NR1 C0 Domain By Ca super(2+)/Calmodulin Promotes CaMKII Binding

• Published in: Biochemistry (Easton) Vol. 46; no. 29; pp. 8485 - 8497
• Main Authors: Merrill, MA, Malik, Z, Akyol, Z, Bartos, JA, Leonard, A S, Hudmon, A, Shea, MA, Hell, J W
• Format: Journal Article
• Language: English
• Published: 24.07.2007
• ISSN: 0006-2960
• DOI: 10.1021/bi0623025

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