NFAT5-mediated CACNA1C expression is critical for cardiac electrophysiological development and maturation

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Developmental Biology

Background:

• Calcium entry via L-type calcium channels (LTCC) is crucial for cardiomyocyte contraction.
• CACNA1C, a key LTCC subunit, is vital for ventricular myocyte maturation and developmentally regulated.

Purpose of the Study:

• To identify transcription factors regulating CACNA1C expression during cardiomyocyte development.
• To elucidate the role of Nuclear Factor of Activated T cells 5 (Nfat5) in CACNA1C regulation and cardiac function.

Main Methods:

• Comparative genomics of CACNA1C promoter regions across eight vertebrate species.
• In vitro cardiomyocyte differentiation model (mouse P19cl6 cells).
• siRNA and morpholino-mediated knockdown experiments in mice and zebrafish.
• Gene expression analysis and electrophysiological measurements.

Main Results:

• Identified 138 potential transcription factors for CACNA1C; six were developmentally regulated.
• Nfat5 directly binds to the CACNA1C promoter and activates its transcription.
• Nfat5 knockdown in mouse cardiomyocytes reduced CACNA1C expression and L-type calcium current.
• Nfat5 knockdown in zebrafish resulted in a non-contractile ventricle, which was rescued by CACNA1C or Nfat5 overexpression.

Conclusions:

• NFAT5-mediated CACNA1C expression is evolutionarily conserved.
• NFAT5 is critical for the electrophysiological development and maturation of cardiomyocytes.
• The NFAT5-CACNA1C pathway is essential for proper cardiac function.