TY - JOUR
T1 - Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm
AU - Cerrone, Marina
AU - Montnach, Jerome
AU - Lin, Xianming
AU - Zhao, Yan Ting
AU - Zhang, Mingliang
AU - Agullo-Pascual, Esperanza
AU - Leo-Macias, Alejandra
AU - Alvarado, Francisco J.
AU - Dolgalev, Igor
AU - Karathanos, Thomas V.
AU - Malkani, Kabir
AU - Van Opbergen, Chantal J.M.
AU - Van Bavel, Joanne J.A.
AU - Yang, Hua Qian
AU - Vasquez, Carolina
AU - Tester, David
AU - Fowler, Steven
AU - Liang, Fengxia
AU - Rothenberg, Eli
AU - Heguy, Adriana
AU - Morley, Gregory E.
AU - Coetzee, William A.
AU - Trayanova, Natalia A.
AU - Ackerman, Michael J.
AU - Van Veen, Toon A.B.
AU - Valdivia, Hector H.
AU - Delmar, Mario
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-00127-0
DO - 10.1038/s41467-017-00127-0
M3 - Article
C2 - 28740174
AN - SCOPUS:85026427979
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 106
ER -