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Nat Commun. 2017 Jul 24;8(1):106. doi: 10.1038/s41467-017-00127-0.

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

Author information

1
Leon H Charney Division of Cardiology, NYU School of Medicine, 520 First Avenue, New York, NY, 10016, USA.
2
Center for Arrhythmia Research, Division of Cardiology, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA.
3
Department of Molecular and Integrative Physiology, University of Michigan, 2800 Plymouth Road, Ann Arbor, MI, 48109, USA.
4
Genome Technology Center, NYU School of Medicine, 520 First Avenue, New York, NY, 10016, USA.
5
Institute for Computational Medicine and Department of Biomedical Engineering, Johns Hopkins University, 3400N Charles St., Baltimore, MD, 21218, USA.
6
Department of Medical Physiology Division of Heart & Lungs University Medical Centre Utrecht, Yalelaan 50, 3584CM, Utrecht, The Netherlands.
7
Department of Pediatrics, NYU School of Medicine, 520 First Avenue, New York, NY, 10016, USA.
8
Departments of Cardiovascular Diseases/Division of Heart Rhythm Services, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
9
Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
10
Department of Molecular Pharmacology and Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
11
Department of Cell Biology and Microscopy Core, NYU School of Medicine, 520 First Avenue, New York, NY, 10016, USA.
12
Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, 520 First Avenue, New York, NY, 10016, USA.
13
Departments of Pediatrics, Physiology & Neuroscience and Biochemistry and Molecular Pharmacology, NYU School of Medicine, 520 First Avenue, New York, NY, 10016, USA.
14
Leon H Charney Division of Cardiology, NYU School of Medicine, 520 First Avenue, New York, NY, 10016, USA. Mario.delmar@nyumc.org.

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.It is believed that mutations in desmosomal adhesion complex protein plakophilin 2 (PKP2) cause arrhythmia due to loss of cell-cell communication. Here the authors show that PKP2 controls the expression of proteins involved in calcium cycling in adult mouse hearts, and that lack of PKP2 can cause arrhythmia in a structurally normal heart.

PMID:
28740174
PMCID:
PMC5524637
DOI:
10.1038/s41467-017-00127-0
[Indexed for MEDLINE]
Free PMC Article

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