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J. Biol. Chem., Vol. 283, Issue 23, 15577-15588, June 6, 2008

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New Determinant for the Ca_Vβ₂ Subunit Modulation of the Ca_V1.2 Calcium Channel^*

From the NIA, National Institutes of Health, Baltimore, Maryland 21224

Ca_vβ subunits support voltage gating of Ca_v1.2 calcium channels and play important role in excitation-contraction coupling. The common central membrane-associated guanylate kinase (MAGUK) region of Ca_vβ binds to the -interaction domain (AID) and the IQ motif of the pore-forming _1C subunit, but these two interactions do not explain why the cardiac Ca_vβ₂ subunit splice variants differentially modulate inactivation of Ca²⁺ currents (I_Ca). Previously we described β_2g, a functionally active splice variant of human Ca_vβ₂ lacking MAGUK. By deletion analysis of β_2g, we have now identified a 41-amino acid C-terminal essential determinant (β₂CED) that stimulates I_Ca in the absence of Ca_vβ subunits and conveys a +20-mV shift in the peak of the I_Ca-voltage relationship. The β₂CED is targeted by _1C to the plasma membrane, forms a complex with _1C but does not bind to AID. Electrophysiology and binding studies point to the calmodulin-interacting LA/IQ region in the _1C subunit C terminus as a functionally relevant β₂CED binding site. The β₂CED interacts with LA/IQ in a Ca²⁺- and calmodulin-independent manner and need LA, but not IQ, to activate the channel. Deletion/mutation analyses indicated that each of the three Ca_vβ₂/_1C interactions is sufficient to support I_Ca. However, β₂CED does not support Ca²⁺-dependent inactivation, suggesting that interactions of MAGUK with AID and IQ are crucial for Ca²⁺-induced inactivation. The β₂CED is conserved only in Ca_vβ₂ subunits. Thus, β₂CED constitutes a previously unknown integrative part of the multifactorial mechanism of Ca_vβ₂-subunit differential modulation of the Ca_v1.2 calcium channel that in β_2g occurs without MAGUK.

Received for publication, March 13, 2008

^* This work was supported, in whole or in part, by the National Institutes of Health NIA Intramural Research Program. 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: 5600 Nathan Shock Dr., Baltimore, MD 21224. Tel.: 410-558-8343; Fax: 410-558-8318; E-mail: soldatovN{at}grc.nia.nih.gov.

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