Fibroblast growth factor homologous factors tune arrhythmogenic late NaV1.5 current in calmodulin binding-deficient...

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Ion Channel Regulation

Background:

• Calmodulin (Ca2+-binding protein) is known to regulate sodium channel function, but its in vivo role in cardiac late sodium current is unclear.
• Late sodium current (late INa) contributes to cardiac arrhythmias and heart failure.
• The NaV1.5 interactome, including associated regulatory proteins, is critical for precise control of cardiac electrophysiology.

Purpose of the Study:

• To investigate the role of calmodulin and the NaV1.5 interactome in regulating late INa in cardiomyocytes.
• To elucidate the mechanisms preventing increased late INa in specific NaV1.5 channel mutants.
• To explore potential endogenous factors for therapeutic targeting of late INa.

Main Methods:

• Generated cardiac-specific transgenic mice expressing human NaV1.5 channels with mutations affecting calmodulin binding (IQ/AA) or lidocaine resistance (F1759A).
• Assessed ventricular repolarization, arrhythmias, and late INa in cardiomyocytes from these mice.
• Utilized proximity labeling and proteomic analysis to identify NaV1.5 interactors, focusing on fibroblast growth factor homologous factors (FHFs).

Main Results:

• IQ/AA mutant mice showed normal repolarization and no increased late INa, indicating calmodulin binding prevents this.
• F1759A mutant mice exhibited increased late INa, prolonged repolarization, and spontaneous arrhythmias.
• FGF13 specifically reduced late INa in IQ/AA mutant cardiomyocytes, suggesting FHFs prevent excessive late INa.

Conclusions:

• Calmodulin binding to NaV1.5 C-terminus is essential for preventing increased late INa and arrhythmias in vivo.
• Endogenous FHFs, like FGF13, may act as endogenous regulators to suppress late INa in cardiomyocytes.
• Targeting these endogenous mechanisms offers a novel therapeutic strategy for conditions associated with excessive late INa.