Role of sodium-calcium exchanger (Ncx1) in embryonic heart development: A Transgenic Rescue?

Simon J. Conway, Agnieszka Kruzynska-Frejtag, Jian Wang, Rhonda Rogers, Paige L. Kneer, Hongmei Chen, Tony Creazzo, Donald R. Menick, Srinagesh V. Koushik

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Na+/Ca2+ exchanger (Ncx-1) is highly expressed in cardiomyocytes, is thought to be required to maintain a low intracellular Ca2+ concentration, and may play a role in excitation-contraction coupling. Significantly, targeted deletion of Ncx-1 results in Ncx1-null embryos that do not have a spontaneously beating heart and die in utero. Ultrastructural analysis revealed gross anomalies in the Ncx1-null contractile apparatus, but physiologic analysis showed normal field-stimulated Ca2+ transients, suggesting that Ncx-1 function may not be critical for Ca2+ extrusion from the cytosol as previously thought. Using caffeine to empty the intracellular Ca2+ stores, we show that the sarcoplasmic reticulum is not fully functional within the 9.5-dpc mouse heart, indicating that the sarcoplasmic reticulum is unlikely to account for the unexpected maintenance of intracellular Ca2+ homeostasis. Using the Ncx1-lacZ reporter, our data indicate restricted expression patterns of Ncx1 and that Ncx1 is highly expressed within the conduction system, suggesting Ncx1 may be required for spontaneous pacemaking activity. To test this hypothesis, we used transgenic mice overexpressing one of the two known adult Ncx1 isoforms under the control of the cardiac-specific α-myosin heavy chain promoter to restore Ncx1 expression within the Ncx1-null hearts. Results indicate that the transgenic reexpression of one Ncx1 isoform was unable to rescue the lethal null mutant phenotype. Furthermore, our in situ results indicate that both known adult Ncx1 isoforms are coexpressed within the embryonic heart, suggesting that effective transgenic rescue may require the presence of both isoforms within the developing heart.

Original languageEnglish (US)
Pages (from-to)268-281
Number of pages14
JournalAnnals of the New York Academy of Sciences
Volume976
StatePublished - Jan 1 2002
Externally publishedYes

Keywords

  • Cardiac Na/Ca exchanger
  • Embryonic heartbeat
  • Gene expression
  • Knockout mouse mutant
  • Transgenic rescue

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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  • Cite this

    Conway, S. J., Kruzynska-Frejtag, A., Wang, J., Rogers, R., Kneer, P. L., Chen, H., Creazzo, T., Menick, D. R., & Koushik, S. V. (2002). Role of sodium-calcium exchanger (Ncx1) in embryonic heart development: A Transgenic Rescue? Annals of the New York Academy of Sciences, 976, 268-281.