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J. Biol. Chem., Vol. 280, Issue 33, 29612-29619, August 19, 2005

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Molecular Mechanism for Divergent Regulation of Ca_v1.2 Ca²⁺ Channels by Calmodulin and Ca²⁺-binding Protein-1^*

Hong Zhou, Kuai Yu, Kelly L. McCoy, and Amy Lee

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

Ca²⁺-binding protein-1 (CaBP1) and calmodulin (CaM) are highly related Ca²⁺-binding proteins that directly interact with, and yet differentially regulate, voltage-gated Ca²⁺ channels. Whereas CaM enhances inactivation of Ca²⁺ currents through Ca_v1.2 (L-type) Ca²⁺ channels, CaBP1 completely prevents this process. How CaBP1 and CaM mediate such opposing effects on Ca_v1.2 inactivation is unknown. Here, we identified molecular determinants in the ₁-subunit of Ca_v1.2 (₁1.2) that distinguish the effects of CaBP1 and CaM on inactivation. Although both proteins bind to a well characterized IQ-domain in the cytoplasmic C-terminal domain of ₁1.2, mutations of the IQ-domain that significantly weakened CaM and CaBP1 binding abolished the functional effects of CaM, but not CaBP1. Pulldown binding assays revealed Ca²⁺-independent binding of CaBP1 to the N-terminal domain (NT) of ₁1.2, which was in contrast to Ca²⁺-dependent binding of CaM to this region. Deletion of the NT abolished the effects of CaBP1 in prolonging Ca_v1.2 Ca²⁺ currents, but spared Ca²⁺-dependent inactivation due to CaM. We conclude that the NT and IQ-domains of ₁1.2 mediate functionally distinct interactions with CaBP1 and CaM that promote conformational alterations that either stabilize or inhibit inactivation of Ca_v1.2.

Received for publication, April 18, 2005 , and in revised form, June 13, 2005.

^* This work was supported by National Institutes of Health Grants NS044922 and AG021723 (to A. L.) and by the Whitehall Foundation. 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.

Both authors contributed equally to this work.

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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