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

Autor: Adriana Heguy, Marina Cerrone, Eli Rothenberg, Joanne J.A. Van Bavel, Esperanza Agullo-Pascual, Mingliang Zhang, Alejandra Leo-Macias, Kabir Malkani, Hua Qian Yang, Jérôme Montnach, Thomas V. Karathanos, William A. Coetzee, Yan-Ting Zhao, Gregory E. Morley, Héctor H. Valdivia, Feng-Xia Liang, Natalia A. Trayanova, Michael J. Ackerman, Xianming Lin, Francisco J. Alvarado, David J. Tester, Toon A.B. van Veen, Carolina Vasquez, Mario Delmar, Chantal J. M. van Opbergen, Steven J. Fowler, Igor Dolgalev
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
medicine.medical_specialty
Chemistry(all)
Transcription
Genetic
Science
Blotting
Western
General Physics and Astronomy
Gene Expression
030204 cardiovascular system & hematology
Biology
Physics and Astronomy(all)
Ryanodine receptor 2
Biochemistry
General Biochemistry
Genetics and Molecular Biology
Calcium in biology
Article
03 medical and health sciences
0302 clinical medicine
Desmosome
ANK2
Internal medicine
Gene expression
medicine
Animals
Humans
Myocytes
Cardiac
Calcium metabolism
Mice
Knockout
Multidisciplinary
Microscopy
Confocal
Biochemistry
Genetics and Molecular Biology(all)
Reverse Transcriptase Polymerase Chain Reaction
Myocardium
Arrhythmias
Cardiac
Heart
General Chemistry
3. Good health
Cell biology
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Triadin
Knockout mouse
Calcium
Plakophilins
Genetics and Molecular Biology(all)
Zdroj: Nature Communications, Vol 8, Iss 1, Pp 1-16 (2017)
Nature Communications
Nature Communications [E], 8(1). Nature Publishing Group
ISSN: 2041-1723
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: