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The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the

Juliane Stieber1, Stefan Herrmann, Susanne Feil

  • 1Institut für Pharmakologie und Toxikologie, Technische Universität München, Biedersteinerstrasse 29, D-80802 Munich, Germany. steiber@ipt.med.tu-muenchen.de

Proceedings of the National Academy of Sciences of the United States of America
|December 6, 2003
PubMed

Insights

The hyperpolarization-activated, cyclic nucleotide-gated cation channel 4 (HCN4) is crucial for heart development. Mice lacking HCN4 channels exhibit severe cardiac conduction defects and embryonic lethality, underscoring its essential role in pacemaker function.

Area of Science:

  • Cardiovascular Physiology
  • Ion Channel Biology
  • Developmental Biology

Background:

  • Hyperpolarization-activated, cyclic nucleotide-gated cation currents (If/Ih) are generated by the HCN channel family.
  • These currents are implicated in pacemaker activity in the heart and brain, resting potential control, and neuronal plasticity.
  • The specific physiological role of the HCN4 isoform in cardiac development remained largely unknown.

Purpose of the Study:

  • To investigate the essential role of HCN4 in the developing cardiac conduction system.
  • To determine the impact of HCN4 deficiency on cardiac pacemaker activity and embryonic survival.

Main Methods:

  • Analysis of HCN4 expression in wild-type embryonic hearts.
  • Generation and study of global and cardiomyocyte-selective HCN4-deficient mouse models.
  • Electrophysiological recordings of cardiac cells from wild-type and mutant embryos.

Main Results:

  • HCN4 is highly expressed in the developing sinoatrial node region.
  • HCN4-deficient mice exhibited embryonic lethality between days 9.5-11.5.
  • A significant reduction (85%) in If current was observed in cardiomyocytes from mutant embryos, leading to slower heart contractions and impaired cAMP stimulation.
  • Mature pacemaker potentials were absent in HCN4-deficient embryos, while primitive potentials persisted.

Conclusions:

  • HCN4 channels are essential for the proper generation of pacemaker potentials in the developing sinoatrial node.
  • HCN4 is indispensable for the functional maturation of the cardiac conduction system during embryogenesis.
  • The absence of HCN4 leads to severe cardiac dysfunction and embryonic lethality.

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