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Myotonic Dystrophy Protein Kinase Phosphorylates Phospholamban and Regulates Calcium Uptake in Cardiomyocyte Sarcoplasmic Reticulum
Ist Teil von
The Journal of biological chemistry, 2005-03, Vol.280 (9), p.8016-8021
Ort / Verlag
United States: American Society for Biochemistry and Molecular Biology
Erscheinungsjahr
2005
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
Myotonic dystrophy (DM) is caused by a CTG expansion in the 3â²-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 Ca 2+ -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 Ca 2+ 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.