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J. Biol. Chem., Vol. 280, Issue 47, 39316-39323, November 25, 2005

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Differential Modulation of Ca²⁺/Calmodulin-dependent Protein Kinase II Activity by Regulated Interactions with N-Methyl-D-aspartate Receptor NR2B Subunits and -Actinin^*

From the Department of Molecular Physiology and Biophysics, Center for Molecular Neurosciences and The Vanderbilt-Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615

Neuronal Ca²⁺/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 -actinin bind comparable, approximately stoichiometric amounts of Thr²⁸⁶-autophosphorylated CaMKII, 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 Thr²⁸⁶-autophosphorylated CaMKII bind to -actinin with similar efficacy, but autophosphorylation at Thr^305/306 or Ca²⁺/calmodulin binding significantly reduce this binding. Moreover, -actinin antagonizes CaMKII activation by Ca²⁺/calmodulin, as assessed by autophosphorylation and phosphorylation of a peptide substrate. CaMKII binding to densin (1247-1542) is partially independent of Thr²⁸⁶ autophosphorylation and is unaffected by Ca²⁺-independent autophosphorylation or Ca²⁺/calmodulin. In addition, the CaMKII binding domain of densin-180 has little effect on CaMKII activity. In contrast, the interaction of CaMKII with NR2B requires either Thr²⁸⁶ autophosphorylation or the binding of both Ca²⁺/calmodulin and adenine nucleotides. NR2B inhibits both the Ca²⁺/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.

Received for publication, July 27, 2005 , and in revised form, September 14, 2005.

^* This work was supported in part by National Institutes of Health Research Grants MH63232 and NS44082 (to R. J. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by National Institutes of Health Training Grants F32-MH068129 and 5T32-DK07563.

² Supported in part by National Institutes of Health Training Grant 5T32-DK07563.

³ To whom correspondence should be addressed: Rm. 724 RRB, Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232-0615. Tel.: 615-936-1630; Fax: 615-322-7236; E-mail: roger.colbran{at}vanderbilt.edu.

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