Differential Modulation of Ca super(2+)/Calmodulin-dependent Protein Kinase II Activity by Regulated Interactions with N-Methyl-D-aspartate Receptor NR2B Subunits and alpha -Actinin

• Published in: The Journal of biological chemistry 2005-11, Vol.280 (47), p.39316-39323
• Main Authors: Robison, A J, Bartlett, Ryan K, Bass, Martha A, Colbran, Roger J
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X

Neuronal Ca super(2+)/calmodulin-dependent protein kinase II (CaMKII) interacts with several prominent dendritic spine proteins, which have been termed CaMKII-associated proteins. The NR2B subunit of N-methyl-D-aspartate (NMDA)-type glutamate receptor, densin-180, and alpha -actinin bind comparable, approximately stoichiometric amounts of Thr super(286)-autophosphorylated CaMKII alpha , forming a ternary complex (Robison, A. J., Bass, M. A., Jiao, Y., Macmillan, L. B., Carmody, L. C., Bartlett, R. K., and Colbran, R. J. (2005) J. Biol. Chem. 280, 35329-35336), but their impacts on CaMKII function are poorly understood. Here we show that these interactions are differentially regulated and exert distinct effects on CaMKII activity. Nonphosphorylated and Thr super(286)-autophosphorylated CaMKII bind to alpha -actinin with similar efficacy, but autophosphorylation at Thr super(305/306) or Ca super(2+)/calmodulin binding significantly reduce this binding. Moreover, alpha -actinin antagonizes CaMKII activation by Ca super(2+)/calmodulin, as assessed by autophosphorylation and phosphorylation of a peptide substrate. CaMKII binding to densin (1247-1542) is partially independent of Thr super(286) autophosphorylation and is unaffected by Ca super(2+)-independent autophosphorylation or Ca super(2+)/calmodulin. In addition, the CaMKII binding domain of densin-180 has little effect on CaMKII activity. In contrast, the interaction of CaMKII alpha with NR2B requires either Thr super(286) autophosphorylation or the binding of both Ca super(2+)/calmodulin and adenine nucleotides. NR2B inhibits both the Ca super(2+)/calmodulin-dependent and autonomous activities of CaMKII by a mechanism that is competitive with autocamtide-2 substrate, non-competitive with syntide-2 substrate, and uncompetitive with respect to ATP. In combination, these data suggest that dynamically regulated interactions with CaMKII-associated proteins could play pleiotropic roles in finetuning CaMKII signaling in defined subcellular compartments.