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 & 7 others Gregory E. Morley, William A. Coetzee, Natalia A. Trayanova, Michael John Ackerman, Toon A.B. Van Veen, Hector H. Valdivia, Mario Delmar

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number106
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Fingerprint

Plakophilins
rhythm
Transcription
genes
calcium
coding
Genes
arrhythmia
Calcium
cycles
mutations
adhesion
knockout mice
cells
homeostasis
Cell adhesion
Cell Adhesion
Cardiac Arrhythmias
Calsequestrin
Ankyrins

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Cerrone, M., Montnach, J., Lin, X., Zhao, Y. T., Zhang, M., Agullo-Pascual, E., ... Delmar, M. (2017). Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. Nature Communications, 8(1), [106]. https://doi.org/10.1038/s41467-017-00127-0

Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. / Cerrone, Marina; Montnach, Jerome; Lin, Xianming; Zhao, Yan Ting; Zhang, Mingliang; Agullo-Pascual, Esperanza; Leo-Macias, Alejandra; Alvarado, Francisco J.; Dolgalev, Igor; Karathanos, Thomas V.; Malkani, Kabir; Van Opbergen, Chantal J.M.; Van Bavel, Joanne J.A.; Yang, Hua Qian; Vasquez, Carolina; Tester, David; Fowler, Steven; Liang, Fengxia; Rothenberg, Eli; Heguy, Adriana; Morley, Gregory E.; Coetzee, William A.; Trayanova, Natalia A.; Ackerman, Michael John; Van Veen, Toon A.B.; Valdivia, Hector H.; Delmar, Mario.

In: Nature Communications, Vol. 8, No. 1, 106, 01.12.2017.

Research output: Contribution to journalArticle

Cerrone, M, Montnach, J, Lin, X, Zhao, YT, Zhang, M, Agullo-Pascual, E, Leo-Macias, A, Alvarado, FJ, Dolgalev, I, Karathanos, TV, Malkani, K, Van Opbergen, CJM, Van Bavel, JJA, Yang, HQ, Vasquez, C, Tester, D, Fowler, S, Liang, F, Rothenberg, E, Heguy, A, Morley, GE, Coetzee, WA, Trayanova, NA, Ackerman, MJ, Van Veen, TAB, Valdivia, HH & Delmar, M 2017, 'Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm', Nature Communications, vol. 8, no. 1, 106. https://doi.org/10.1038/s41467-017-00127-0
Cerrone, Marina ; Montnach, Jerome ; Lin, Xianming ; Zhao, Yan Ting ; Zhang, Mingliang ; Agullo-Pascual, Esperanza ; Leo-Macias, Alejandra ; Alvarado, Francisco J. ; Dolgalev, Igor ; Karathanos, Thomas V. ; Malkani, Kabir ; Van Opbergen, Chantal J.M. ; Van Bavel, Joanne J.A. ; Yang, Hua Qian ; Vasquez, Carolina ; Tester, David ; Fowler, Steven ; Liang, Fengxia ; Rothenberg, Eli ; Heguy, Adriana ; Morley, Gregory E. ; Coetzee, William A. ; Trayanova, Natalia A. ; Ackerman, Michael John ; Van Veen, Toon A.B. ; Valdivia, Hector H. ; Delmar, Mario. / Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. In: Nature Communications. 2017 ; Vol. 8, No. 1.
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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 John

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AU - Valdivia, Hector H.

AU - Delmar, Mario

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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.

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