Calcium sensing receptor regulates cardiomyocyte function through nuclear calcium

Authors

  • Xin Zhong,

    Corresponding author
    1. Department of Pathophysiology, Harbin Medical University, Harbin 150086, People's Republic of China
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  • Jun Liu,

    Corresponding author
    1. Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, People's Republic of China
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  • Fanghao Lu,

    1. Department of Pathophysiology, Harbin Medical University, Harbin 150086, People's Republic of China
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  • Yuwen Wang,

    1. Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, People's Republic of China
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  • Yajun Zhao,

    1. Department of Pathophysiology, Harbin Medical University, Harbin 150086, People's Republic of China
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  • Shiyun Dong,

    1. Department of Pathophysiology, Harbin Medical University, Harbin 150086, People's Republic of China
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  • Xiaoning Leng,

    1. Department of Pathophysiology, Harbin Medical University, Harbin 150086, People's Republic of China
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  • Jing Jia,

    1. Department of Pathophysiology, Harbin Medical University, Harbin 150086, People's Republic of China
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  • Huan Ren,

    1. Department of Immunology, Harbin Medical University, Harbin 150086, People's Republic of China
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  • Changqing Xu,

    Corresponding author
    1. Department of Pathophysiology, Harbin Medical University, Harbin 150086, People's Republic of China
    2. Bio-Pharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin 150086, People's Republic of China
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  • Weihua Zhang

    Corresponding author
    1. Department of Pathophysiology, Harbin Medical University, Harbin 150086, People's Republic of China
    2. Bio-Pharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin 150086, People's Republic of China
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These authors contributed equally to this work.

Correspondence may be addressed to either of these authors (email zhangwh116@hotmail.com or xucq45@126.com).

Abstract

Nuclear Ca2+ plays a pivotal role in the regulation of gene expression. IP3 (inositol-1,4,5-trisphosphate) is an important regulator of nuclear Ca2+. We hypothesized that the CaR (calcium sensing receptor) stimulates nuclear Ca2+ release through IICR (IP3-induced calcium release) from perinuclear stores. Spontaneous Ca2+ oscillations and the spark frequency of nuclear Ca2+ were measured simultaneously in NRVMs (neonatal rat ventricular myocytes) using confocal imaging. CaR-induced nuclear Ca2+ release through IICR was abolished by inhibition of CaR and IP3Rs (IP3 receptors). However, no effect on the inhibition of RyRs (ryanodine receptors) was detected. The results suggest that CaR specifically modulates nuclear Ca2+ signalling through the IP3R pathway. Interestingly, nuclear Ca2+ was released from perinuclear stores by CaR activator-induced cardiomyocyte hypertrophy through the Ca2+-dependent phosphatase CaN (calcineurin)/NFAT (nuclear factor of activated T-cells) pathway. We have also demonstrated that the activation of the CaR increased the NRVM protein content, enlarged cell size and stimulated CaN expression and NFAT nuclear translocation in NRVMs. Thus, CaR enhances the nuclear Ca2+ transient in NRVMs by increasing fractional Ca2+ release from perinuclear stores, which is involved in cardiac hypertrophy through the CaN/NFAT pathway.

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