Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification

Area of Science:

• Cardiovascular physiology
• Molecular cardiology
• Ion channel biophysics

Background:

• Cardiac inward rectifier current (I(K1)) is crucial for cardiac rhythm, and its dysregulation is linked to severe arrhythmias.
• Flecainide, an antiarrhythmic drug, can have proarrhythmic effects and also treats arrhythmias associated with decreased I(K1) due to Kir2.1 channel mutations (Andersen syndrome).

Purpose of the Study:

• To elucidate the electrophysiological and molecular mechanisms underlying flecainide's effect on Kir2.1 channels and I(K1).
• To investigate flecainide's interaction site and its potential therapeutic role in Andersen syndrome.

Main Methods:

• Electrophysiological recordings of I(Kir2.1) and I(K1) in ventricular myocytes.
• Molecular characterization of flecainide-channel interactions, including site-directed mutagenesis.
• Cell surface expression assays to assess functional channel trafficking.

Main Results:

• Flecainide enhances outward I(Kir2.1) by decreasing intracellular polyamine affinity, thereby reducing inward rectification.
• The interaction involves the HI loop of the Kir2.1 cytoplasmic domain, with Cys311 being critical for flecainide's effects.
• Flecainide increases membrane expression of functional Kir2.1 channels, an effect dependent on Cys311.
• Flecainide rescues specific Andersen syndrome mutations (R67W) but not others (R218W).

Conclusions:

• Flecainide modulates I(K1) by interacting with Kir2.1 channels, offering a mechanism for its therapeutic and proarrhythmic actions.
• Cys311 is a key residue mediating flecainide's effects on Kir2.1 channel gating, rectification, and trafficking.
• Flecainide shows promise as a pharmacological rescue agent for specific forms of Andersen syndrome.