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, Pilar Ruiz-Lozano

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)8016-8021
Number of pages6
JournalJournal of Biological Chemistry
Volume280
Issue number9
DOIs
Publication statusPublished - Mar 4 2005

ASJC Scopus subject areas

  • Biochemistry

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