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J. Biol. Chem., Vol. 280, Issue 9, 8016-8021, March 4, 2005

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Myotonic Dystrophy Protein Kinase Phosphorylates Phospholamban and Regulates Calcium Uptake in Cardiomyocyte Sarcoplasmic Reticulum^*

Perla Kaliman, Daniele Catalucci¶, Jason T. Lam¶, Richard Kondo¶, José Carlos Paz Gutiérrez, Sita Reddy||, Manuel Palacín**, Antonio Zorzano, Kenneth R. Chien¶, and Pilar Ruiz-Lozano¶

From the Institute of Molecular Medicine, University of California, San Diego, California 92093, ^||Institute for Genetic Medicine, University of Southern California, Los Angeles, California 90033, and ^**Institut de Recerca Biomèdica, Parc Científic de Barcelona, Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, E-08028 Barcelona, Spain

Myotonic dystrophy (DM) is caused by a CTG expansion in the 3'-untranslated region of a protein kinase gene (DMPK). Cardiovascular disease is one of the most prevalent causes of death in DM patients. Electrophysiological studies in cardiac muscles from DM patients and from DMPK^-/- mice suggested that DMPK is critical to the modulation of cardiac contractility and to the maintenance of proper cardiac conduction activity. However, there are no data regarding the molecular signaling pathways involved in DM heart failure. Here we show that DMPK expression in cardiac myocytes is highly enriched in the sarcoplasmic reticulum (SR) where it colocalizes with the ryanodine receptor and phospholamban (PLN), a muscle-specific SR Ca²⁺-ATPase (SERCA2a) inhibitor. Coimmunoprecipitation studies showed that DMPK and PLN can physically associate. Furthermore, purified wild-type DMPK, but not a kinase-deficient mutant (K110A DMPK), phosphorylates PLN in vitro. Subsequent studies using the DMPK^-/- mice demonstrated that PLN is hypo-phosphorylated in SR vesicles from DMPK^-/- mice compared with wild-type mice both in vitro and in vivo. Finally, we show that Ca²⁺ uptake in SR is impaired in ventricular homogenates from DMPK^-/- mice. Together, our data suggest the existence of a novel regulatory DMPK pathway for cardiac contractility and provide a molecular mechanism for DM heart pathology.

Received for publication, November 12, 2004 , and in revised form, December 6, 2004.

^* This work has been supported by National Institutes of Health Grants HL065484 (to P. R.-L.) and SAF2001-3500 from the Ministerio de Ciencia y Tecnología, Spain (to P. K.). 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.

To whom correspondence should be addressed: Dept. de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, E-08028 Barcelona, Spain. Tel.: 34-93-4034700; Fax: 34-93-4021559; E-mail: pkaliman{at}ub.edu.

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