Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: signaling through dynamic allosteric coupling

Neuron. 2002 Oct 24;36(3):451-61. doi: 10.1016/s0896-6273(02)00968-6.


Signal transduction in neurons is a dynamic process, generally thought to be driven by transient changes in the concentration of second messengers. Here we describe a novel regulatory mechanism in which the dynamics of signaling through cyclic AMP are mediated by activity-dependent changes in the affinity of the hyperpolarization-activated, cation nonselective (HCN) channels for cAMP, rather than by changes in cAMP concentration. Due to the allosteric coupling of channel opening and ligand binding, changes in cellular electrical activity that alter the opening of the HCN channels modify the binding of static, basal levels of cAMP. These changes in ligand binding produce long-lasting changes in channel function which can contribute to the regulation of rhythmic firing patterns.

Publication types

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

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology*
  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Animals
  • Central Nervous System / metabolism*
  • Cerebral Cortex / metabolism
  • Cyclic AMP / metabolism*
  • Cyclic AMP / pharmacology
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Female
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels / drug effects
  • Ion Channels / metabolism*
  • Kinetics
  • Models, Neurological
  • Muscle Proteins / drug effects
  • Muscle Proteins / metabolism*
  • Neural Pathways / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Oocytes
  • Reaction Time / drug effects
  • Reaction Time / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Thalamus / metabolism
  • Xenopus laevis


  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Muscle Proteins
  • Cyclic AMP