Calcium extrusion is critical for cardiac morphogenesis and rhythm in embryonic zebrafish hearts

Ebert, A.M., Hume, G.L., Warren, K.S., Cook, N.P., Burns, C.G., Mohideen, M.A., Siegal, G., Yelon, D., Fishman, M.C., and Garrity, D.M.
Proceedings of the National Academy of Sciences of the United States of America   102(49): 17705-17710 (Journal)
Registered Authors
Fishman, Mark C., Garrity, Deborah, Mohideen, Manzoor Pallithotangal, Warren, Kerri S., Yelon, Deborah
heart development, arrhythmia, sodium calcium exchanger, Ca2+-ATPase
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Calcium/metabolism*
  • Calcium/pharmacology
  • Calcium-Transporting ATPases/genetics
  • Calcium-Transporting ATPases/metabolism
  • Heart/drug effects
  • Heart/embryology*
  • Heart/physiopathology*
  • Humans
  • Microscopy, Electron, Transmission
  • Molecular Sequence Data
  • Morphogenesis/physiology*
  • Mutation/genetics
  • Myocardial Contraction/physiology*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Sodium-Calcium Exchanger/chemistry
  • Sodium-Calcium Exchanger/genetics
  • Sodium-Calcium Exchanger/metabolism
  • Zebrafish/embryology*
16314582 Full text @ Proc. Natl. Acad. Sci. USA
Calcium entry into myocytes drives contraction of the embryonic heart. To prepare for the next contraction, myocytes must extrude calcium from intracellular space via the Na(+)/Ca(2+) exchanger (NCX1) or sequester it into the sarcoplasmic reticulum, via the sarcoplasmic reticulum Ca(2+)-ATPase2 (SERCA2). In mammals, defective calcium extrusion correlates with increased intracellular calcium levels and may be relevant to heart failure and sarcoplasmic dysfunction in adults. We report here that mutation of the cardiac-specific NCX1 (NCX1h) gene causes embryonic lethal cardiac arrhythmia in zebrafish tremblor (tre) embryos. The tre ventricle is nearly silent, whereas the atrium manifests a variety of arrhythmias including fibrillation. Calcium extrusion defects in tre mutants correlate with severe disruptions in sarcomere assembly, whereas mutations in the L-type calcium channel that abort calcium entry do not produce this phenotype. Knockdown of SERCA2 activity by morpholino-mediated translational inhibition or pharmacological inhibition causes embryonic lethality due to defects in cardiac contractility and morphology but, in contrast to tre mutation, does not produce arrhythmia. Analysis of intracellular calcium levels indicates that homozygous tre embryos develop calcium overload, which may contribute to the degeneration of cardiac function in this mutant. Thus, the inhibition of NCX1h versus SERCA2 activity differentially affects the pathophysiology of rhythm in the developing heart and suggests that relative levels of NCX1 and SERCA2 function are essential for normal development.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes