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NFAT5-mediated CACNA1C expression is critical for cardiac electrophysiological development and maturation

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An Erratum to this article was published on 12 August 2016

Abstract

Entry of calcium into cardiomyocyte via L-type calcium channel (LTCC) is fundamental to cardiac contraction. CACNA1C, a type of LTCC and a hallmark of a matured ventricular myocyte, is developmentally regulated. Here, we identified 138 potential transcription factors by a comparative genomic study on 5-kb promoter regions of CACNA1C gene across eight vertebrate species, and showed that six factors were developmentally regulated with the expression of Cacna1c in mouse P19cl6 in vitro cardiomyocyte differentiation model. We further demonstrated that the nuclear factor of activated T cells 5 (Nfat5) bound to a consensus sequence TGGAAGCGTTC and activated the transcription of Cacna1c. The siRNA-mediated knockdown of Nfat5 suppressed the expression of Cacna1c and decreased L-type calcium current in mouse neonatal cardiomyocytes. Furthermore, morpholino-mediated knockdown of nfat5 in zebrafish prohibited the expression of cacna1c and resulted in a non-contractile ventricle, while over-expression of either cacna1c or nfat5 rescued this impaired phenotype. Thus, NFAT5-mediated expression of CACNA1C is evolutionarily conserved and critical for cardiac electrophysiological development and maturation of cardiomyocyte.

Key message

  • Nfat5 binds to a consensus sequence TGGAAGCGTTC in the promoter of Cacna1c.

  • Nfat5 activates the transcription of Cacna1c.

  • Nfat5 knockdown suppresses Cacna1c expression, decreases L-type calcium current, and results in non-beating ventricle.

  • NFAT5-mediated expression of CACNA1C is evolutionarily conserved.

  • NFAT5-mediated CACNA1C expression is critical for cardiac electrophysiological development and maturation.

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Acknowledgments

We thank Dr. Ricardo Dolmetsch for kindly providing us CACNA1C cDNA. This study was supported by grants from the National Basic Research Program of the Chinese Ministry of Science and Technology (973 grant nos.: 2013CB530700 and 2007CB512103 to XLT and 2012CB945101 to BZ).

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Authors and Affiliations

  1. Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, 5 Yiheyuan Road, Beijing, 100871, China

    Wei Li, Ke Xu, Fan Yang, Gu-Yan Zheng, Huiqing Cao & Xiao-Li Tian

  2. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, 5 Yiheyuan Road, Beijing, 100871, China

    Nai-Zhong Zheng & Bo Zhang

  3. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, 100101, China

    Qi Yuan, Lei Gu & Guang-Ju Ji

  4. School of Electronics Engineering and Computer Science, Peking University, 5 Yiheyuan Road, Beijing, 100871, China

    Guo-Jie Luo

  5. Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Chun Fan

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  1. Wei Li
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Li, W., Zheng, NZ., Yuan, Q. et al. NFAT5-mediated CACNA1C expression is critical for cardiac electrophysiological development and maturation. J Mol Med 94, 993–1002 (2016). https://doi.org/10.1007/s00109-016-1444-x

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