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Propafenone blocks human cardiac Kir2.x channels by decreasing the negative electrostatic charge in the cytoplasmic

Irene Amorós1, Pablo Dolz-Gaitón, Ricardo Gómez

  • 1Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.

Biochemical Pharmacology
|May 8, 2013
PubMed

Insights

The antiarrhythmic drug propafenone inhibits human cardiac inward rectifier current (IK1) by binding to Kir2.x channels. This action, particularly on Kir2.3 and IK1, offers potential for treating arrhythmias.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Pharmacology
  • Ion Channel Biophysics

Background:

  • Human cardiac inward rectifier current (IK1) is crucial for cardiac electrical stability.
  • Kir2.x channels generate IK1, and their pharmacology is not fully understood.
  • Inhibiting IK1 is a potential antiarrhythmic strategy for fibrillatory arrhythmias.

Purpose of the Study:

  • To characterize the electrophysiological and molecular mechanisms of propafenone's inhibition of Kir2.x channels and IK1.
  • To determine the potency and specificity of propafenone against different Kir2.x subtypes.
  • To elucidate the binding site and mode of action of propafenone on Kir2.x channels.

Main Methods:

  • Transient transfection of wild-type and mutated human Kir2.x channels in CHO and HEK-293 cells.
  • Macroscopic and single-channel current recordings using the patch-clamp technique.
  • Blind docking and site-directed mutagenesis to identify propafenone's binding site.

Main Results:

  • Propafenone inhibited IKir2.x and IK1 at concentrations >1μM, with potency order Kir2.3∼IK1>Kir2.2>Kir2.1.
  • Blockade was independent of extracellular K+ but increased with decreased intracellular K+.
  • Propafenone decreased inward rectification, favored subconductance levels, and reduced PIP2-channel affinity.
  • Propafenone binds to the cytoplasmic domain of Kir2.x channels, involving Arg228 and Arg260 (Kir2.1).

Conclusions:

  • Propafenone acts as a potent inhibitor of human cardiac IK1 via Kir2.x channels.
  • The drug binds to the cytoplasmic domain, modulating channel gating and PIP2 interaction.
  • These findings provide a molecular basis for propafenone's antiarrhythmic potential against specific arrhythmias.

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