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Related Experiment Videos

Pathways regulating Na+/Ca2+ exchanger expression in the heart.

Donald R Menick1, Lin Xu, Christina Kappler

  • 1Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, South Carolina 29425, USA. menickd@musc.edu

Annals of the New York Academy of Sciences
|December 28, 2002
PubMed
Summary

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The study reveals how cardiac cells regulate the Na(+)/Ca(2+) exchanger (NCX1) gene. JNK pathways control basal expression, while ERK and p38 pathways influence NCX1 upregulation, particularly after alpha-adrenergic stimulation.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Gene Regulation

Background:

  • The Na(+)/Ca(2+) exchanger (NCX1) plays a critical role in cardiac function and is transcriptionally regulated during cardiac stress.
  • Mitogen-activated protein kinases (MAPKs) are implicated in the upregulation of NCX1 gene expression following pressure overload in adult cardiomyocytes.

Purpose of the Study:

  • To elucidate the specific molecular pathways, including JNK, ERK, and p38, involved in the transcriptional regulation of the NCX1 gene in cardiac cells.
  • To differentiate the roles of various MAPKs in basal NCX1 expression versus alpha-adrenergic-stimulated NCX1 upregulation.

Main Methods:

  • Adenoviral gene delivery was employed to manipulate MAPK signaling pathways in adult cardiocytes.
  • Specific inhibitors (UO126 for ERK) and overexpression constructs (DN-JNK, activated MKK-3) were used to probe pathway activation.

Related Experiment Videos

  • Reporter gene assays were utilized to assess NCX1 gene upregulation.

    • Main Results:

    • Inhibition of ERK activation partially reduced alpha-adrenergic-induced NCX1 upregulation (by 30%).
    • Overexpression of dominant-negative JNK (DN-JNK) decreased basal NCX1 expression.
    • Overexpression of activated MKK-3 was sufficient to induce NCX1 reporter gene upregulation, mimicking alpha-adrenergic stimulation.

    Conclusions:

    • JNK signaling is essential for maintaining basal NCX1 gene expression in the heart.
    • Both ERK and p38 pathways contribute to the alpha-adrenergic-stimulated upregulation of NCX1.
    • p38 pathway activation alone is sufficient to drive NCX1 gene upregulation in cardiac cells.