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Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm

Author

Listed:
  • Marina Cerrone

    (NYU School of Medicine)

  • Jerome Montnach

    (NYU School of Medicine)

  • Xianming Lin

    (NYU School of Medicine)

  • Yan-Ting Zhao

    (University of Michigan)

  • Mingliang Zhang

    (NYU School of Medicine)

  • Esperanza Agullo-Pascual

    (NYU School of Medicine)

  • Alejandra Leo-Macias

    (NYU School of Medicine)

  • Francisco J. Alvarado

    (University of Michigan)

  • Igor Dolgalev

    (NYU School of Medicine)

  • Thomas V. Karathanos

    (Johns Hopkins University)

  • Kabir Malkani

    (NYU School of Medicine)

  • Chantal J.M. Van Opbergen

    (Department of Medical Physiology Division of Heart & Lungs University Medical Centre Utrecht)

  • Joanne J.A. van Bavel

    (Department of Medical Physiology Division of Heart & Lungs University Medical Centre Utrecht)

  • Hua-Qian Yang

    (NYU School of Medicine)

  • Carolina Vasquez

    (NYU School of Medicine)

  • David Tester

    (Windland Smith Rice Sudden Death Genomics Laboratory
    Windland Smith Rice Sudden Death Genomics Laboratory
    Windland Smith Rice Sudden Death Genomics Laboratory)

  • Steven Fowler

    (NYU School of Medicine)

  • Fengxia Liang

    (NYU School of Medicine)

  • Eli Rothenberg

    (NYU School of Medicine)

  • Adriana Heguy

    (NYU School of Medicine)

  • Gregory E. Morley

    (NYU School of Medicine)

  • William A. Coetzee

    (NYU School of Medicine)

  • Natalia A. Trayanova

    (Johns Hopkins University)

  • Michael J. Ackerman

    (Windland Smith Rice Sudden Death Genomics Laboratory
    Windland Smith Rice Sudden Death Genomics Laboratory
    Windland Smith Rice Sudden Death Genomics Laboratory)

  • Toon A.B. van Veen

    (Department of Medical Physiology Division of Heart & Lungs University Medical Centre Utrecht)

  • Hector H. Valdivia

    (University of Michigan)

  • Mario Delmar

    (NYU School of Medicine)

Abstract

Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell–cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for CaV1.2) and Trdn (coding for triadin), and protein levels of calsequestrin-2 (Casq2). These factors combined lead to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias that are prevented by flecainide treatment. We propose a previously unrecognized arrhythmogenic mechanism related to PKP2 expression and suggest that mutations in PKP2 in humans may cause life-threatening arrhythmias even in the absence of structural disease.

Suggested Citation

  • Marina Cerrone & Jerome Montnach & Xianming Lin & Yan-Ting Zhao & Mingliang Zhang & Esperanza Agullo-Pascual & Alejandra Leo-Macias & Francisco J. Alvarado & Igor Dolgalev & Thomas V. Karathanos & Kab, 2017. "Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm," Nature Communications, Nature, vol. 8(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00127-0
    DOI: 10.1038/s41467-017-00127-0
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    Cited by:

    1. Aina Lluch & Jessica Latorre & Angela Serena-Maione & Isabel Espadas & Estefanía Caballano-Infantes & José M. Moreno-Navarrete & Núria Oliveras-Cañellas & Wifredo Ricart & María M. Malagón & Alejandro, 2023. "Impaired Plakophilin-2 in obesity breaks cell cycle dynamics to breed adipocyte senescence," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    2. Allen C. T. Teng & Liyang Gu & Michelle Paola & Robert Lakin & Zachary J. Williams & Aaron Au & Wenliang Chen & Neal I. Callaghan & Farigol Hakem Zadeh & Yu-Qing Zhou & Meena Fatah & Diptendu Chatterj, 2022. "Tmem65 is critical for the structure and function of the intercalated discs in mouse hearts," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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