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 Heguy, Gregory E. Morley, William A. Coetzee, Natalia A. Trayanova, Michael J. Ackerman, Toon A.B. van Veen, Hector H. Valdivia and Mario Delmar ()
Additional contact information
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
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
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

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00127-0

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