Targeted inactivation of the sodium‐calcium exchanger (Ncx1) results in the lack of a heartbeat and abnormal myofibrillar organization

Abstract

Contraction of cardiac muscle is triggered by an intracellular buildup of Ca 2+ during excitation‐contraction (E‐C) coupling. The Na + /Ca 2+ exchanger ( Ncx1 ) is highly expressed in cardiomyocytes and is thought to serve a housekeeping function by maintaining a low intracellular Ca 2+ concentration. However, its role in E‐C coupling is controversial. To determine the precise role of Na + /Ca 2+ exchange in development of the mammalian heart, we used gene targeting to delete Ncx1 . Heterozygous mice are normal and fertile, whereas Ncx1 ‐null embryos are growth‐retarded and survive to 11.0 days postcoitum but lack a spontaneously beating heart. Moreover, normal heart morphogenesis (specification, looping, and chamber formation) occurred relatively normally within Ncx1 ‐null embryos. In addition, Ncx1 ‐nulls displayed relatively normal transient Ca 2+ signals when electrically stimulated. This suggests that the Ca 2+ delivery mechanism was fundamentally intact, and that Ncx1 ‐null cardiomyocytes can regulate intracellular Ca 2+ concentrations despite the absence of Ncx1 . However, ultrastructural analysis revealed that Ncx1 ‐null cardiomyocytes have a complete lack of organized myofibrils and Z‐lines when compared with normal littermates. These data demonstrate that Ncx‐1 is a Ca 2+ ‐ gene that is essential for normal cardiomyocyte development and function and may serve as an animal model for functionally related human congenital heart defects.