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J. Biol. Chem., Vol. 279, Issue 13, 12456-12461, March 26, 2004

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Calcium Current in Rat Cardiomyocytes Is Modulated by the Carboxyl-terminal Ahnak Domain^*

Julio Alvarez¶, Jana Hamplova||, Annette Hohaus**, Ingo Morano**, Hannelore Haase**, and Guy Vassort

From the Physiopathologie Cardiovasculaire, INSERM U-390, CHU Arnaud de Villeneuve, F-34295 Montpellier Cedex 5, France, ^**Max Delbrück Center for Molecular Medicine (MDC), D-13125 Berlin, Germany, Institute of Cardiology, La Habana, Cuba, and Johannes Müller Institute for Physiology, Humboldt University (Charité), D-10117 Berlin, Germany

Ahnak, a protein of 5643 amino acids, interacts with the regulatory -subunit of cardiac calcium channels and with F-actin. Recently, we defined the binding sites among the protein partners in the carboxyl-terminal domain of ahnak. Here we further narrowed down the ₂-interaction sites to the carboxyl-terminal 188 amino acids of ahnak by the recombinant ahnak protein fragments P3 (amino acids 5456-5556) and P4 (amino acids 5556-5643). The effects of these P3 and P4 fragments on the calcium current were investigated under whole-cell patch clamp conditions on rat ventricular cardiomyocytes. P4 but not P3 increased significantly the current amplitude by 22.7 ± 5% without affecting its voltage dependence. The slow component of calcium current inactivation was slowed down by both P3 and P4, whereas only P3 slowed significantly the fast one. The composite recombinant protein fragment P3-P4 induced similar modifications to the ones induced by each of the ahnak fragments. In the presence of carboxyl-terminal ahnak protein fragments, isoprenaline induced a similar relative increase in current amplitude and shift in current kinetics. The actin-stabilizing agents, phalloidin and jasplakinolide, did not modify the effects of these ahnak protein fragments on calcium current in control conditions nor in the presence of isoprenaline. Hence, our results suggest that the functional effects of P3, P4, and P3-P4 on calcium current are mediated by targeting the ahnak-₂-subunit interaction rather than by targeting the ahnak-F-actin interaction. More specifically they suggest that binding of the ₂-subunit to the endogenous subsarcolemmal giant ahnak protein re-primes the _1C/₂-subunit interaction and that the ahnak-derived proteins relieve the ₂-subunit from this inhibition.

Received for publication, November 6, 2003 , and in revised form, January 5, 2004.

^* This work was supported in part by Region Languedoc-Roussillon, Association Française Contre les Myopathies, Fondation de France, and Deutsche Forschungsgemeinschaft Grant Ha 1779/4-1 and 1779/-2. 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.

^¶ Visiting scientist at INSERM U-390.

^|| Supported by an INSERM "Programme Orange."

To whom correspondence should be addressed. Tel.: 33-4-67-41-52-41; Fax: 33-4-67-41-52-42; E-mail: vassort{at}montp.inserm.fr.

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