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J. Biol. Chem., Vol. 282, Issue 11, 8464-8473, March 16, 2007

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Caldendrin, a Neuron-specific Modulator of Ca_v/1.2 (L-type) Ca²⁺ Channels^*

From the Department of Pharmacology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322

EF-hand Ca²⁺-binding proteins such as calmodulin and CaBP1 have emerged as important regulatory subunits of voltage-gated Ca²⁺ channels. Here, we show that caldendrin, a variant of CaBP1 enriched in the brain, interacts with and distinctly modulates Ca_v1.2 (L-type) voltage-gated Ca²⁺ channels relative to other Ca²⁺-binding proteins. Caldendrin binds to the C-terminal IQ-domain of the pore-forming ₁-subunit of Ca_v1.2 (₁1.2) and competitively displaces calmodulin and CaBP1 from this site. Compared with CaBP1, caldendrin causes a more modest suppression of Ca²⁺-dependent inactivation of Ca_v1.2 through a different subset of molecular determinants. Caldendrin does not bind to the N-terminal domain of ₁1.2, a site that is critical for functional interactions of the channel with CaBP1. Deletion of the N-terminal domain inhibits CaBP1, but spares caldendrin modulation of Ca_v1.2 inactivation. In contrast, mutations of the IQ-domain abolish physical and functional interactions of caldendrin and Ca_v1.2, but do not prevent channel modulation by CaBP1. Using antibodies specific for caldendrin and Ca_v1.2, we show that caldendrin coimmunoprecipitates with Ca_v1.2 from the brain and colocalizes with Ca_v1.2 in somatodendritic puncta of cortical neurons in culture. Our findings reveal functional diversity within related Ca²⁺-binding proteins, which may enhance the specificity of Ca²⁺ signaling by Ca_v1.2 channels in different cellular contexts.

Received for publication, December 12, 2006 , and in revised form, January 15, 2007.

^* This work was supported in part by Grant NS044922 (to A. L.) from the National Institutes of Health and grants from the Whitehall Foundation and the Emory University Research Committee. 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 To whom correspondence should be addressed: Dept. of Pharmacology, Emory University School of Medicine, 5123 Rollins Research Bldg., 1510 Clifton Rd., Atlanta, GA 30322. Tel.: 404-727-5991; Fax: 404-727-0365; E-mail: alee{at}pharm.emory.edu.

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