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.

Details

Title
Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm
Author
Cerrone, Marina 1 ; Montnach, Jerome 1 ; Lin, Xianming 1 ; Yan-Ting, Zhao 2 ; Zhang, Mingliang 1 ; Agullo-Pascual, Esperanza 1 ; Leo-Macias, Alejandra 1 ; Alvarado, Francisco J 3   VIAFID ORCID Logo  ; Dolgalev, Igor 4   VIAFID ORCID Logo  ; Karathanos, Thomas V 5 ; Malkani, Kabir 1   VIAFID ORCID Logo  ; Chantal JM Van Opbergen 6 ; van Bavel, Joanne JA 6 ; Hua-Qian, Yang 7 ; Vasquez, Carolina 1 ; Tester, David 8 ; Fowler, Steven 1 ; Liang, Fengxia 9 ; Rothenberg, Eli 10 ; Heguy, Adriana 4 ; Morley, Gregory E 1 ; Coetzee, William A 11 ; Trayanova, Natalia A 5 ; Ackerman, Michael J 8 ; Toon AB van Veen 6 ; Valdivia, Hector H 2 ; Delmar, Mario 1 

1  Leon H Charney Division of Cardiology, NYU School of Medicine, New York, NY, USA 
2  Center for Arrhythmia Research, Division of Cardiology, University of Michigan, Ann Arbor, MI, USA 
3  Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA 
4  Genome Technology Center, NYU School of Medicine, New York, NY, USA 
5  Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA 
6  Department of Medical Physiology Division of Heart & Lungs University Medical Centre Utrecht, Utrecht, The Netherlands 
7  Department of Pediatrics, NYU School of Medicine, New York, NY, USA 
8  Departments of Cardiovascular Diseases/Division of Heart Rhythm Services, Windland Smith Rice Sudden Death Genomics Laboratory, Rochester, MN, USA; Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Rochester, MN, USA 
9  Department of Cell Biology and Microscopy Core, NYU School of Medicine, New York, NY, USA 
10  Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, USA 
11  Departments of Pediatrics, Physiology & Neuroscience and Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, USA 
Pages
1-16
Publication year
2017
Publication date
Jul 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-00127-0
ProQuest document ID
1924544117
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.