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Mutagenesis and Functional Analysis of Ion Channels Heterologously Expressed in Mammalian Cells
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Published on: October 1, 2010

Ethanol enhances human hyperpolarization-activated cyclic nucleotide-gated currents.

Yongjun Chen1, Pan Wu, Xinrong Fan

  • 1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

Alcoholism, Clinical and Experimental Research
|May 18, 2012
PubMed
Summary

Excessive ethanol (EtOH) consumption increases sudden cardiac death risk. This study reveals EtOH enhances hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents, potentially explaining EtOH-induced arrhythmias.

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Area of Science:

  • Cardiology
  • Molecular Biology
  • Pharmacology

Background:

  • Excessive ethanol (EtOH) consumption is linked to sudden cardiac death.
  • Hyperpolarization-activated cyclic nucleotide-gated (HCN) current (I(f)) influences sinoatrial node cell pacemaker activity.
  • Mechanisms of EtOH's proarrhythmic effects remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms by which EtOH affects HCN channels and SA node function.
  • To elucidate the role of EtOH in cardiac arrhythmia induction.

Main Methods:

  • Rabbit SA node preparations and isolated pacemaker cells were used to record transmembrane potentials and I(f).
  • Whole-cell patch clamp and two-electrode voltage clamp techniques were employed.
  • Human HCN2 (hHCN2) and HCN4 channels were expressed in Xenopus oocytes for functional analysis.

Main Results:

  • EtOH increased SA node cell firing frequency reversibly; ivabradine attenuated this effect.
  • EtOH enhanced I(f) and HCN currents in a concentration-dependent manner (EC50 ~18-22 mM).
  • EtOH altered HCN channel activation kinetics and voltage dependence, with differential effects on HCN2 and HCN4 channels.

Conclusions:

  • EtOH directly interacts with hHCN2 and hHCN4 channels.
  • This interaction enhances channel function and alters gating properties.
  • Findings provide molecular insights into EtOH's proarrhythmic potential.