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

Pollak Adam J.; Haghighi Kobra; Kunduri SwatiArvanitis Demetrios A.Bidwell Philip A.Liu Guan-ShengSingh Vivek P.Gonzalez David J.Sanoudou DespinaWiley Sandra E.Dixon Jack E.Kranias Evangelia G.

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

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

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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 after contractions 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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2017年第34期|9098-9103|共6页
作者
Pollak Adam J.; Haghighi Kobra; Kunduri SwatiArvanitis Demetrios A.Bidwell Philip A.Liu Guan-ShengSingh Vivek P.Gonzalez David J.Sanoudou DespinaWiley Sandra E.Dixon Jack E.Kranias Evangelia G.;
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作者单位

Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA;

Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA;

Acad Athens, Ctr Basic Res Biomed Res Fdn, Dept Mol Biol, Athens 11527, Greece;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
histidine-rich calcium-binding protein; Fam20C kinase; heart; arrhythmia; phosphorylation;

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

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