Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node

J Physiol. 2003 Jun 1;549(Pt 2):347-59. doi: 10.1113/jphysiol.2002.027698. Epub 2003 Apr 17.


'Funny-' (f-) channels of cardiac sino-atrial node (SAN) cells are key players in the process of pacemaker generation and mediate the modulatory action of autonomic transmitters on heart rate. The molecular components of f-channels are the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. Of the four HCN isoforms known, two (HCN4 and HCN1) are expressed in the rabbit SAN at significant levels. However, the properties of f-channels of SAN cells do not conform to specific features of the two isoforms expressed locally. For example, activation kinetics and cAMP sensitivity of native pacemaker channels are intermediate between those reported for HCN1 and HCN4. Here we have explored the possibility that both HCN4 and HCN1 isoforms contribute to the native If in SAN cells by co-assembling into heteromeric channels. To this end, we used heterologous expression in human embryonic kidney (HEK) 293 cells to investigate the kinetics and cAMP response of the current generated by co-transfected (HCN4 + HCN1) and concatenated (HCN4-HCN1 (4-1) tandem or HCN1-HCN4 (1-4) tandem) rabbit constructs and compared them with those of the native f-current from rabbit SAN. 4-1 tandem, but not co-transfected, currents had activation kinetics approaching those of If; however, the activation range of 4-1 tandem channels was more negative than that of the f-channel and their cAMP sensitivity were poorer (although that of 1-4 tandem channels was normal). Co-transfection of 4-1 tandem channels with minK-related protein 1(MiRP1) did not alter their properties. HCN1 and HCN4 may contribute to native f-channels, but a 'context'-dependent mechanism is also likely to modulate the channel properties in native tissues.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cyclic AMP / pharmacology
  • Cyclic Nucleotide-Gated Cation Channels
  • Electrophysiology
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels / chemistry
  • Ion Channels / metabolism*
  • Ion Channels / physiology
  • Kinetics
  • Muscle Proteins / chemistry
  • Muscle Proteins / metabolism*
  • Muscle Proteins / physiology
  • Nerve Tissue Proteins*
  • Potassium Channels / metabolism
  • Potassium Channels, Voltage-Gated*
  • Rabbits
  • Sinoatrial Node / cytology
  • Sinoatrial Node / metabolism*


  • Cyclic Nucleotide-Gated Cation Channels
  • HCN1 protein, human
  • HCN4 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Muscle Proteins
  • Nerve Tissue Proteins
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • potassium channel protein I(sk)
  • Cyclic AMP