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Microelectrode Array Recording of Sinoatrial Node Firing Rate to Identify Intrinsic Cardiac Pacemaking Defects in Mice
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Microelectrode Array Recording of Sinoatrial Node Firing Rate to Identify Intrinsic Cardiac Pacemaking Defects in Mice

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Hysteresis in human HCN4 channels: a crucial feature potentially affecting sinoatrial node pacemaking

Yong-Fu Xiao1, Natalie Chandler, Halina Dobrzynski

  • 1Cardiac Rhythm Disease Management, Medtronic Inc., Mounds View, MN 55112, USA. yong-fu.xiao@medtronic.com

Sheng Li Xue Bao : [Acta Physiologica Sinica]
|February 25, 2010
PubMed

Insights

The study found that human HCN4 channels, predominant in the heart's pacemaker, exhibit voltage-dependent hysteresis. Cyclic AMP modifies this behavior, suggesting a key role in regulating cardiac rhythm.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Ion Channel Biophysics

Background:

  • Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are crucial for regulating cardiac rhythm and rate.
  • The HCN4 subtype is the predominant HCN channel in the human sinoatrial node (SAN).
  • Voltage-dependent hysteresis in HCN channels influences their gating properties.

Purpose of the Study:

  • To investigate the electrophysiological properties of human HCN4 (hHCN4) channels.
  • To determine if hHCN4 exhibits voltage-dependent hysteresis.
  • To examine the modulatory effect of cAMP on hHCN4 channel activity and hysteresis.

Main Methods:

  • Single-cell patch-clamp electrophysiology in HEK293 cells stably expressing hHCN4.
  • Voltage-clamp analysis using triangular ramp and action potential clamp protocols.
  • Quantitative real-time RT-PCR to assess HCN subtype expression in human cardiac tissue.

Main Results:

  • hHCN4 current (Ih) activation showed a depolarizing shift with hyperpolarized holding potentials.
  • hHCN4 exhibited voltage-dependent hysteresis, confirmed by ramp and action potential clamp protocols.
  • cAMP enhanced Ih and shifted activation, altering the intrinsic hysteresis behavior of hHCN4.
  • HCN4 is the predominant HCN subtype (75%) in human SAN tissue, with HCN1 (21%) and HCN2 (3%) also present.

Conclusions:

  • Human HCN4 channels display voltage-dependent hysteresis, contrary to previous suggestions for slower HCN subtypes.
  • cAMP significantly modulates hHCN4 hysteresis, impacting its electrophysiological function.
  • HCN4 hysteresis is likely a critical factor in human SAN pacemaking activity.

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