@article{3056672,
    title = "Phosphorylation of serine96 of histidine-rich calcium-binding protein by the Fam20C kinase functions to prevent cardiac arrhythmia",
    author = "Pollak, A.J. and Haghighi, K. and Kunduri, S. and Arvanitis, D.A. and Bidwell, P.A. and Liu, G.-S. and Singh, V.P. and Gonzalez, D.J. and Sanoudou, D. and Wiley, S.E. and Dixon, J.E. and Kranias, E.G.",
    journal = "PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA",
    year = "2017",
    volume = "114",
    number = "34",
    pages = "9098-9103",
    publisher = "National Academy of Sciences",
    doi = "10.1073/pnas.1706441114",
    keywords = "calcium binding protein;  family with sequence similarity 20C;  histidine rich calcium binding protein;  isoprenaline;  protein kinase;  sarcoplasmic reticulum calcium transporting adenosine triphosphatase;  sarcoplasmic reticulum calcium transporting adenosine triphosphatase 2a;  serine;  triadin;  unclassified drug;  calcium binding protein;  casein kinase I;  FAM20C protein, human;  HRC protein, human;  sarcoplasmic reticulum calcium transporting adenosine triphosphatase;  scleroprotein;  serine, adult;  animal experiment;  animal tissue;  Article;  cardiac muscle cell;  congestive cardiomyopathy;  CRISPR Cas system;  enzyme phosphorylation;  gene editing;  heart arrhythmia;  heart protection;  heart tissue;  human;  human cell;  human tissue;  immunoprecipitation;  mouse;  nonhuman;  polyacrylamide gel electrophoresis;  priority journal;  secretory pathway;  Western blotting;  amino acid sequence;  animal;  cell culture;  genetics;  heart arrhythmia;  knockout mouse;  metabolism;  mutation;  phosphorylation;  rat;  sarcoplasmic reticulum;  transgenic mouse;  tumor cell line, Amino Acid Sequence;  Animals;  Arrhythmias, Cardiac;  Calcium-Binding Proteins;  Casein Kinase I;  Cell Line, Tumor;  Cells, Cultured;  Extracellular Matrix Proteins;  Humans;  Mice, Knockout;  Mice, Transgenic;  Mutation;  Myocytes, Cardiac;  Phosphorylation;  Rats;  Sarcoplasmic Reticulum;  Sarcoplasmic Reticulum Calcium-Transporting ATPases;  Serine",
    abstract = "Precise Ca cycling through the sarcoplasmic reticulum (SR), a Ca storage organelle, is critical for proper cardiac muscle function. This cycling initially involves SR release of Ca via the ryanodine receptor, which is regulated by its interacting proteins junctin and triadin. The sarco/endoplasmic reticulum Ca ATPase (SERCA) pump then refills SR Ca stores. Histidine-rich Ca-binding protein (HRC) resides in the lumen of the SR, where it contributes to the regulation of Ca cycling by protecting stressed or failing hearts. The common Ser96Ala human genetic variant of HRC strongly correlates with life-threatening ventricular arrhythmias in patients with idiopathic dilated cardiomyopathy. However, the underlying molecular pathways of this disease remain undefined. Here, we demonstrate that family with sequence similarity 20C (Fam20C), a recently characterized protein kinase in the secretory pathway, phosphorylates HRC on Ser96. HRC Ser96 phosphorylation was confirmed in cells and human hearts. Furthermore, a Ser96Asp HRC variant, which mimics constitutive phosphorylation of Ser96, diminished delayed aftercontractions in HRC null cardiac myocytes. This HRC phosphomimetic variant was also able to rescue the aftercontractions elicited by the Ser96Ala variant, demonstrating that phosphorylation of Ser96 is critical for the cardioprotective function of HRC. Phosphorylation of HRC on Ser96 regulated the interactions of HRC with both triadin and SERCA2a, suggesting a unique mechanism for regulation of SR Ca homeostasis. This demonstration of the role of Fam20C-dependent phosphorylation in heart disease will open new avenues for potential therapeutic approaches against arrhythmias. © 2017, National Academy of Sciences. All rights reserved."
}