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Carbon monoxide inhibits inward rectifier potassium channels in cardiomyocytes

Shenghui Liang1, Quanyi Wang2, Weiwei Zhang1

  • 1Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Peking 100871, China.

Nature Communications
|August 15, 2014
PubMed

Insights

Carbon monoxide (CO) prevents ventricular fibrillation (VF) by prolonging action potential duration. CO inhibits specific inward-rectifying potassium (Kir) channels, offering a new target for preventing VF after heart attack.

Area of Science:

  • Cardiovascular Research
  • Molecular Cardiology
  • Ion Channel Physiology

Background:

  • Reperfusion-induced ventricular fibrillation (VF) poses a significant threat to patients post-myocardial infarction.
  • Carbon monoxide (CO), endogenously produced by heme oxygenase in cardiomyocytes, is known to prevent VF via an unelucidated mechanism.

Purpose of the Study:

  • To elucidate the mechanism by which carbon monoxide (CO) prevents reperfusion-induced ventricular fibrillation (VF).
  • To identify the specific ion channels targeted by CO in cardiomyocytes.

Main Methods:

  • Investigated the effect of CO on action potential duration (APD) in cardiomyocytes.
  • Examined CO's interaction with various inward-rectifying potassium (Kir) channel subtypes (Kir2.1, Kir2.2, Kir2.3) using electrophysiological recordings in both native cardiomyocytes and heterologous expression systems (HEK-293 cells).
  • Assessed the direct molecular interaction between CO and Kir2.3 channels, focusing on their relationship with phosphatidylinositol (4,5)-bisphosphate (PIP2).

Main Results:

  • CO was found to significantly prolong action potential duration (APD) in cardiomyocytes.
  • CO selectively inhibited Kir2.2 and Kir2.3 channels, while having no significant effect on Kir2.1 channels.
  • CO directly binds to and inhibits Kir2.3 by disrupting its interaction with the second messenger PIP2.

Conclusions:

  • CO prolongs cardiac action potential duration by inhibiting specific inward-rectifying potassium channels, namely Kir2.2 and Kir2.3.
  • Cardiac Kir2.2 and Kir2.3 channels represent promising therapeutic targets for the prevention of reperfusion-induced ventricular fibrillation.

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