HCN Channels: Structure, Cellular Regulation and Physiological Function

Cell Mol Life Sci. 2009 Feb;66(3):470-94. doi: 10.1007/s00018-008-8525-0.


Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels belong to the superfamily of voltage-gated pore loop channels. HCN channels are unique among vertebrate voltage-gated ion channels, in that they have a reverse voltage-dependence that leads to activation upon hyperpolarization. In addition, voltage-dependent opening of these channels is directly regulated by the binding of cAMP. HCN channels are encoded by four genes (HCN1-4) and are widely expressed throughout the heart and the central nervous system. The current flowing through HCN channels, designated I(h) or I(f), plays a key role in the control of cardiac and neuronal rhythmicity ("pacemaker current"). In addition, I(h) contributes to several other neuronal processes, including determination of resting membrane potential, dendritic integration and synaptic transmission. In this review we give an overview on structure, function and regulation of HCN channels. Particular emphasis will be laid on the complex roles of these channels for neuronal function and cardiac rhythmicity.

Publication types

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

MeSH terms

  • Animals
  • Binding Sites
  • Biological Clocks / physiology
  • Chlorides / metabolism
  • Cyclic AMP / metabolism
  • Cyclic Nucleotide-Gated Cation Channels / chemistry*
  • Cyclic Nucleotide-Gated Cation Channels / genetics
  • Cyclic Nucleotide-Gated Cation Channels / metabolism*
  • Humans
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channel Gating
  • Learning / physiology
  • Membrane Potentials
  • Myocardial Contraction / physiology
  • Nerve Net / physiology
  • Neurons / cytology
  • Neurons / physiology
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Potassium Channels / chemistry*
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Protein Conformation
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protons
  • Synaptic Transmission / physiology
  • Tissue Distribution
  • Tyrosine / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Chlorides
  • Cyclic Nucleotide-Gated Cation Channels
  • HCN1 protein, human
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Phosphatidylinositol 4,5-Diphosphate
  • Potassium Channels
  • Protein Isoforms
  • Protons
  • Tyrosine
  • Cyclic AMP
  • p38 Mitogen-Activated Protein Kinases