Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages

Nature. 2002 Oct 24;419(6909):837-41. doi: 10.1038/nature01038.


Hyperpolarization-activated cyclic-nucleotide-gated (HCN) ion channels are found in rhythmically firing cells in the brain and in the heart, where the cation current through HCN channels (called I(h) or I(f)) causes these cells to fire repeatedly. These channels are also found in non-pacing cells, where they control resting membrane properties, modulate synaptic transmission, mediate long-term potentiation, and limit extreme hyperpolarizations. HCN channels share sequence motifs with depolarization-activated potassium (Kv) channels, such as the fourth transmembrane segment S4. S4 is the main voltage sensor of Kv channels, in which transmembrane movement of S4 charges triggers the opening of the activation gate. Here, using cysteine accessibility methods, we investigate whether S4 moves in an HCN channel. We show that S4 movement is conserved between Kv and HCN channels, which indicates that S4 is also the voltage sensor in HCN channels. Our results suggest that a conserved voltage-sensing mechanism operates in the oppositely voltage-gated Kv and HCN channels, but that there are different coupling mechanisms between the voltage sensor and activation gate in the two different channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Cations / metabolism
  • Cyclic Nucleotide-Gated Cation Channels
  • Electric Conductivity
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channel Gating*
  • Ion Channels / chemistry
  • Ion Channels / genetics
  • Ion Channels / metabolism*
  • Membrane Potentials
  • Models, Biological
  • Molecular Sequence Data
  • Oocytes / metabolism
  • Patch-Clamp Techniques
  • Potassium Channels / chemistry
  • Potassium Channels / metabolism
  • Sea Urchins
  • Shaker Superfamily of Potassium Channels
  • Structural Homology, Protein
  • Structure-Activity Relationship
  • Xenopus laevis


  • Cations
  • Cyclic Nucleotide-Gated Cation Channels
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Potassium Channels
  • Shaker Superfamily of Potassium Channels