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J. Biol. Chem., Vol. 279, Issue 11, 10206-10214, March 12, 2004

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The eag Potassium Channel Binds and Locally Activates Calcium/Calmodulin-dependent Protein Kinase II^*

Xiu Xia Sun, James J. L. Hodge, Yi Zhou¶, Maidung Nguyen, and Leslie C. Griffith||

From the Department of Biology and Center for Complex Systems, Brandeis University, Waltham, Massachusetts 02454-9110 and the Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6074

Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the regulation of neuronal excitability in many systems. Recent studies suggest that local regulation of membrane potential can have important computational consequences for neuronal function. In Drosophila, CaMKII regulates the eag potassium channel, but if and how this regulation was spatially restricted was unknown. Using coimmunoprecipitation from head extracts and in vitro binding assays, we show that CaMKII and Eag form a stable complex and that association with Eag activates CaMKII independently of CaM and autophosphorylation. Ca²⁺/CaM is necessary to initiate binding of CaMKII to Eag but not to sustain association because binding persists when CaM is removed. The Eag CaMKII-binding domain has homology to the CaMKII autoregulatory region, and the constitutively active CaMKII mutant, T287D, binds Eag Ca²⁺-independently in vitro and in vivo. These results favor a model in which the CaMKII-binding domain of Eag displaces the CaMKII autoinhibitory region. Displacement results in autophosphorylation-independent activation of CaMKII which persists even when Ca²⁺ levels have gone down. Activity-dependent binding to this potassium channel substrate allows CaMKII to remain locally active even when Ca²⁺ levels have dropped, providing a novel mechanism by which CaMKII can regulate excitability locally over long time scales.

Received for publication, September 29, 2003 , and in revised form, December 11, 2003.

^* This work was supported in part by National Institutes of Health Grant R01 GM54408 (to L. C. G.). 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.

^¶ Supported by National Institutes of Health Grant R01 NS17910 (to Irwin B. Levitan). Present address: Dept. of Neurobiology, University of Alabama at Birmingham, 1719 6th Ave. South, SRC 543, Birmingham, AL 35294-0021.

^|| To whom correspondence should be addressed: Dept. of Biology, MS008, Brandeis University, 415 South St., Waltham, MA 02454-9110. Tel.: 781-736-3125; Fax: 781-736-3107; E-mail: griffith{at}brandeis.edu.

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