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Related Experiment Videos

Two pacemaker channels from human heart with profoundly different activation kinetics.

A Ludwig1, X Zong, J Stieber

  • 1Institut für Pharmakologie und Toxikologie der Technischen Universität München, Biedersteiner Strasse 29, 80802 München, Germany.

The EMBO Journal
|May 6, 1999
PubMed
Summary

Researchers identified two human hyperpolarization-activated and cyclic nucleotide-gated cation channel genes, hHCN2 and hHCN4, in the heart. These channels likely generate the fast and slow components of the cardiac pacemaker current (If), crucial for heart rhythm.

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Area of Science:

  • Molecular biology
  • Cardiovascular physiology
  • Ion channel research

Background:

  • Cardiac pacemaking relies on the slow diastolic depolarization phase of action potentials.
  • The hyperpolarization-activated cation current (If) contributes significantly to pacemaker depolarization, exhibiting fast and slow kinetic components.
  • Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels (HCN1-3) were previously identified in the mouse brain.

Purpose of the Study:

  • To identify the molecular components responsible for cardiac pacemaker currents.
  • To characterize novel human HCN channel genes expressed in the heart.

Main Methods:

  • Screening of a human heart cDNA library using a conserved neuronal HCN channel segment.
  • Gene sequencing, localization (chromosome 19p13.3), and exon-intron structure determination for hHCN2.

Related Experiment Videos

  • Northern blot and PCR analyses to determine tissue expression patterns (heart ventricle and atrium).
  • Functional expression of hHCN2 and hHCN4 cDNAs in HEK 293 cells to record hyperpolarization-activated cation currents.

    • Main Results:

    • Two human HCN cDNAs, hHCN2 and hHCN4, were identified and encoded proteins of 889 and 1203 amino acids, respectively.
    • Both hHCN2 and hHCN4 genes are expressed in the human heart (ventricle and atrium).
    • Expressed hHCN2 and hHCN4 channels produced hyperpolarization-activated cation currents in HEK 293 cells, mimicking native cardiac If.
    • hHCN2 currents exhibited fast activation kinetics, while hHCN4 currents showed slow activation kinetics.

    Conclusions:

    • The identified human genes, hHCN2 and hHCN4, are likely the molecular basis for the cardiac pacemaker current (If).
    • hHCN2 and hHCN4 channels correspond to the fast and slow kinetic components of cardiac If, respectively.
    • These findings provide crucial insights into the molecular mechanisms underlying cardiac pacemaking.