LUF7244 plus Dofetilide Rescues Aberrant K_v11.1 Trafficking and Produces Functional I_Kv11.1.

Area of Science:

• Cardiovascular Pharmacology
• Molecular Cardiology
• Ion Channel Physiology

Background:

• Voltage-gated potassium 11.1 (K_v11.1) channels are crucial for cardiac action potential repolarization.
• Drug-induced K_v11.1 channel blockade and trafficking defects can lead to prolonged action potentials and increased risk of sudden cardiac death.
• Existing therapies like dofetilide have limitations due to simultaneous channel blocking effects.

Purpose of the Study:

• To investigate the efficacy of combining dofetilide with LUF7244, a K_v11.1 modulator, in rescuing K_v11.1 trafficking defects.
• To determine if this combination can restore functional K_v11.1 current in cardiomyocytes.
• To explore a novel therapeutic strategy for congenital and acquired long QT syndrome.

Main Methods:

• Utilized Western blot and immunofluorescence microscopy to analyze K_v11.1 trafficking and maturation.
• Treated wild-type and G601S-K_v11.1 expressing cells with pentamidine, dofetilide, and LUF7244.
• Assessed functional K_v11.1 current (I_Kv11.1) using electrophysiology.

Main Results:

• LUF7244 alone did not affect K_v11.1 trafficking.
• Dofetilide, alone or in combination with LUF7244, rescued pentamidine-induced defects in WT K_v11.1 maturation.
• The dofetilide + LUF7244 combination restored K_v11.1 trafficking in G601S mutant cells and increased functional I_Kv11.1.
• Long-term treatment with dofetilide + LUF7244 significantly increased I_Kv11.1 in G601S cells.

Conclusions:

• Combined administration of dofetilide and LUF7244 effectively rescues K_v11.1 trafficking defects.
• This combination restores functional K_v11.1 current, suggesting a potential new therapy for long QT syndrome.
• LUF7244 acts as a K_v11.1 activator, enhancing the therapeutic potential when combined with trafficking correctors.