Regulation of calcium/calmodulin-dependent protein kinase II docking to N-methyl-D-aspartate receptors by calcium/calmodulin and α-actinin

Abstract

Ca2+ influx through the N-methyl-D-aspartate (NMDA)-type glutamate receptor leads to activation and postsynaptic accumulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and ultimately to long term potentiation, which is thought to be the physiological correlate of learning and memory. The NMDA receptor also serves as a CaMKII docking site in dendritic spines with high affinity binding sites located on its NR1 and NR2B subunits. We demonstrate that high affinity binding of CaMKII to NR1 requires autophosphorylation of Thr286. This autophosphorylation reduces the off rate to a level (t1/2 = ∼23 min) that is similar to that observed for dissociation of the T286D mutant CaMKII (t1/2 = ∼30 min) from spines after its glutamate-induced accumulation (Shen, K., Teruel, M. N., Connor, J. H., Shenolikar, S., and Meyer, T. (2000) Nat. Neurosci. 3, 881-886). CaMKII as well as the previously identified NR1 binding partners calmodulin and α-actinin bind to the short C-terminal portion of the CO region of NR1. Like Ca2+/calmodulin, autophosphorylated CaMKII competes with α-actinin-2 for binding to NR1. We conclude that the NR1 C0 region is a key site for recruiting CaMKII to the postsynaptic site, where it may act in concert with calmodulin to modulate the stimulatory role of α-actinin interaction with the NMDA receptor.