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 J; Liang, Fengxia; Rothenberg, Eli; Heguy, Adriana; Morley, Gregory E.; Coetzee, William A.; Trayanova, Natalia A.; Ackerman, Michael J.; Van Veen, Toon A.B.; Valdivia, Hector H.; Delmar, Mario
(2017) Nature Communications [E], volume 8, issue 1
(Article)
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
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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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Keywords: General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: This work was supported by grants RO1-GM57691, RO1-HL134328 and RO1-HL136179 (M.D.), RO1-HL076751 (G.E.M.), RO1HL055438 and RO1 HL120108 (H.H.V.), RO1HL126905 (W.A.C.), RO1-GM108119, R21CA187612, and ACS 130304-RSG-16-241-01-DMC (E.R.), RO1-HL126802 and Pioneer Award DP1-HL123271 (N.A.T.), by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (D.T. and M.J.A.), by support from the Netherlands CardioVascular Research Initiative: the Netherlands Heart Foundation, Netherlands Federation of University Medical Centers, the Netherlands Organization for Health Research and Development and the Royal Netherlands Academy of Sciences (CVON2012-10-PREDICT, to T.A.B.v.V.), by fellowships from the Heart Rhythm Society (J.M.) and the American Heart Association (15POST25550087 to E.A. -P. and 17POST33370050 to H.-Q.Y.) and by a Scientist Development Grant (#14SDG18580014) from the American Heart Association (M.C.). The NYUMC Genome Technology Center facility is partly supported by the Cancer Center Support Grant, P30CA016087, at the Laura and Isaac Perlmutter Cancer Center. Publisher Copyright: © 2017 The Author(s).
(Peer reviewed)
