PDZ domain-binding motif regulates cardiomyocyte compartment-specific NaV1.5 channel expression and function

Area of Science:

• Cardiovascular Physiology
• Molecular Cardiology
• Ion Channel Biology

Background:

• The cardiac sodium channel NaV1.5 is essential for heart electrical activity.
• Its C-terminal PDZ-binding motif (Ser-Ile-Val) interacts with PDZ proteins, forming distinct functional complexes.
• The precise in vivo role and clinical significance of this motif were previously unclear.

Purpose of the Study:

• To investigate the in vivo and clinical impact of the NaV1.5 PDZ-binding motif.
• To elucidate the role of this motif in NaV1.5 expression, function, and cardiac conduction.

Main Methods:

• Generated knock-in mice lacking the SIV motif (ΔSIV).
• Assessed NaV1.5 expression and sodium current (INa) using electrophysiology and optical mapping.
• Investigated channel internalization and degradation pathways (HEK293 cells, MG132).
• Screened patients for mutations within the SIV motif.

Main Results:

• ΔSIV mice showed reduced lateral NaV1.5 expression and INa, leading to increased ventricular conduction anisotropy.
• The SIV motif regulates NaV1.5 degradation, as evidenced by rescue with a proteasome inhibitor.
• A patient with Brugada syndrome harbored a V2016M mutation in the SIV motif, decreasing NaV1.5 expression and INa.

Conclusions:

• The PDZ-binding motif is vital for NaV1.5 localization at the lateral cardiomyocyte membrane and proper ventricular conduction.
• This motif plays a significant role in regulating NaV1.5 protein stability.
• The SIV motif has direct clinical relevance in cardiac diseases like Brugada syndrome.