Mutation in sodium–calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish

doi:10.1073/pnas.0502679102

Mutation in sodium–calcium exchanger 1 (NCX1) causes cardiac fibrillation in zebrafish

^*Department of Molecular, Cell, and Developmental Biology, ^¶Jonsson Comprehensive Cancer Center, ^∥Molecular Biology Institute, ^‡Cardiovascular Research Laboratory, and ^§Departments of Physiology and Medicine, University of California, Los Angeles, CA 90095

Edited by Eric N. Olson, University of Texas Southwestern Medical Center, Dallas, TX, and approved October 10, 2005 (received for review March 31, 2005)

Abstract

Cardiac fibrillation, a form of cardiac arrhythmia, is the most common cause of embolic stroke and death associated with heart failure. The molecular mechanisms underlying cardiac fibrillation are largely unknown. Here we report a zebrafish model for cardiac fibrillation. The hearts of zebrafish tremblor (tre) mutants exhibit chaotic movements and fail to develop synchronized contractions. Calcium imaging showed that normal calcium transients are absent in tre cardiomyocytes, and molecular cloning of the tre mutation revealed that the tre locus encodes the zebrafish cardiac-specific sodium–calcium exchanger (NCX) 1, NCX1h. Forced expression of NCX1h or other calcium-handling molecules restored synchronized heartbeats in tre mutant embryos in a dosage-dependent manner, demonstrating the critical role of calcium homeostasis in maintaining embryonic cardiac function. By creating mosaic zebrafish embryos, we showed that sporadic NCX1h-null cells were not sufficient to disrupt normal cardiac function, but clustered wild-type cardiomyocytes contract in unison in tre mutant hearts. These data signify the essential role of calcium homeostasis and NCX1h in establishing rhythmic contraction in the embryonic zebrafish heart.

Footnotes

↵ ** To whom correspondence should be addressed at: Department of Molecular, Cell, and Developmental Biology, University of California, 621 Charles E. Young Drive South, LSB 5109, Los Angeles, CA 90095. E-mail: chenjn{at}mcdb.ucla.edu.
↵ † A.D.L. and Y.D. contributed equally to this work.
Author contributions: A.D.L. and J.-N.C. designed research; A.D.L., Y.D., X.S., J.C., D.A.N., J.I.G., and J.-N.C. performed research; Y.D., D.A.N., J.I.G., K.D.P., and J.-N.C. contributed new reagents/analytic tools; A.D.L., Y.D., K.D.P., and J.-N.C. analyzed data; and A.D.L. and J.-N.C. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: hpf, hours postfertilization; NCX, sodium–calcium exchanger; PMCA, plasma membrane Ca²⁺-ATPase; SERCA2, sarcoendoplasmic reticular Ca²⁺-ATPase; tre, tremblor.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database [accession nos. AY934775 (NCX1h) and AY934776 (NCX1n)].