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Associated changes in HCN2 and HCN4 transcripts and I(f) pacemaker current in myocytes

Qi Zhang1, Aijie Huang, Yen-Chang Lin

  • 1Center for Cardiovascular and Respiratory Sciences, Department of Physiology, West Virginia University School of Medicine, Morgantown, West Virginia 26506, USA.

Biochimica Et Biophysica Acta
|February 25, 2009
PubMed

Insights

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms 2 and 4 interact to form functional channels. Their varying ratios influence current activation, contributing to tissue-specific heart rhythms.

Area of Science:

  • Cardiovascular Physiology
  • Neuroscience
  • Molecular Biology

Background:

  • Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels generate crucial inward currents.
  • Four HCN isoforms (HCN1-HCN4) exist, with potential for heteromeric channel formation.
  • These channels are vital for rhythmic activities in the brain and heart.

Purpose of the Study:

  • To investigate the functional impact of HCN2 and HCN4 isoform interactions.
  • To determine how varying ratios of HCN2 and HCN4 influence channel kinetics and voltage dependence.
  • To explore the physiological relevance of HCN2/HCN4 heteromerization in cardiac tissue.

Main Methods:

  • Xenopus oocyte expression system with varying HCN2:HCN4 mRNA ratios.
  • Electrophysiological recordings to assess current activation and kinetics.
  • Coimmunoprecipitation assays to confirm protein-protein interactions.
  • Analysis of HCN2 and HCN4 mRNA levels in rat myocytes.

Main Results:

  • Co-expression of HCN2 and HCN4 in oocytes resulted in depolarized current activation and faster kinetics compared to HCN4 homomers.
  • HCN2 and HCN4 proteins associate in adult rat ventricles.
  • Overexpression of HCN4 in myocytes shifted I(f) activation to physiological voltages with faster kinetics.
  • Knockdown of HCN2 in neonatal myocytes led to decreased HCN4 mRNA, and HCN4 overexpression increased HCN2 mRNA.

Conclusions:

  • HCN2 and HCN4 isoforms form functional heteromeric channels.
  • The ratio of HCN2:HCN4 transcripts influences the biophysical properties of the hyperpolarization-activated inward current, I(f).
  • These interactions contribute to tissue-specific electrical properties in the heart.

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