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

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, Kabir Malkani, Chantal J.M. Van Opbergen, Joanne J.A. Van Bavel, Hua Qian Yang, Carolina Vasquez, David Tester, Steven Fowler, Fengxia Liang, Eli Rothenberg, Adriana HeguyGregory E. Morley, William A. Coetzee, Natalia A. Trayanova, Michael J. Ackerman, Toon A.B. Van Veen, Hector H. Valdivia, Mario Delmar

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


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.

Original languageEnglish (US)
Article number106
JournalNature communications
Issue number1
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy


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