PUBLICATION

The Arrhythmogenic Calmodulin Mutation D129G Dysregulates Cell Growth, Calmodulin-dependent Kinase II Activity and Cardiac Function in Zebrafish

Authors
Berchtold, M.W., Zacharias, T., Kulej, K., Wang, K., Torggler, R., Jespersen, T., Chen, J.N., Larsen, M.R., La Cour, J.M.
ID
ZDB-PUB-161107-1
Date
2016
Source
The Journal of biological chemistry   291(52): 26636-26646 (Journal)
Registered Authors
Chen, Jau-Nian
Keywords
Ca2+/calmodulin-dependent protein kinase II (CaMKII), DT40, calcium, calmodulin (CaM), catecholaminergic polymorphic ventricular tachycardia (CPVT), cell signaling, heart failure
MeSH Terms
  • Animals
  • Arrhythmias, Cardiac/genetics*
  • Calcium/metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism*
  • Calmodulin/chemistry
  • Calmodulin/genetics*
  • Calmodulin/metabolism
  • Cell Proliferation/genetics*
  • Cells, Cultured
  • Humans
  • Long QT Syndrome/etiology
  • Long QT Syndrome/metabolism
  • Long QT Syndrome/pathology
  • Mutation/genetics*
  • Myocytes, Cardiac/metabolism
  • Myocytes, Cardiac/pathology
  • Phosphorylation
  • Protein Conformation
  • Tachycardia, Ventricular/etiology
  • Tachycardia, Ventricular/metabolism
  • Tachycardia, Ventricular/pathology*
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish/metabolism
PubMed
27815504 Full text @ J. Biol. Chem.
Abstract
Calmodulin (CaM) is a Ca2+ binding protein modulating multiple targets, several of which are associated with cardiac pathophysiology. Recently, CaM mutations were linked to heart arrhythmia. CaM is crucial for cell growth and viability, yet the effect of the arrhythmogenic CaM mutations on cell viability, as well as heart rhythm, remains unknown, and only a few targets with relevance for heart physiology have been analyzed for their response to mutant CaM. We show that the arrhythmia-associated CaM mutants support growth and viability of DT40 cells in the absence of WT CaM except for the long QT syndrome mutant CaM D129G. Of the six CaM mutants tested (N53I, F89L, D95V, N97S, D129G, and F141L), three showed a decreased activation of Ca2+/CaM-dependent kinase II, most prominently the D129G CaM mutation, which was incapable of stimulating Thr286 autophosphorylation. Furthermore, the CaM D129G mutation led to bradycardia in zebrafish and an arrhythmic phenotype in a subset of the analyzed zebrafish.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes