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Proc Natl Acad Sci U S A. 2017 Aug 22;114(34):9098-9103. doi: 10.1073/pnas.1706441114. Epub 2017 Aug 7.

Phosphorylation of serine96 of histidine-rich calcium-binding protein by the Fam20C kinase functions to prevent cardiac arrhythmia.

Author information

1
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
2
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267.
3
Department of Molecular Biology, Center of Basic Research, Biomedical Research Foundation, Academy of Athens, 11527 Athens, Greece.
4
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
5
Clinical Genomics and Pharmacogenomics Unit, Fourth Department of Internal Medicine, Attikon Hospital-Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
6
Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093; jedixon@ucsd.edu litsa.kranias@uc.edu.
7
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093.
8
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093.
9
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267; jedixon@ucsd.edu litsa.kranias@uc.edu.

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.

KEYWORDS:

Fam20C kinase; arrhythmia; heart; histidine-rich calcium-binding protein; phosphorylation

PMID:
28784772
PMCID:
PMC5576816
DOI:
10.1073/pnas.1706441114
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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