Presynaptic HCN1 channels regulate Cav3.2 activity and neurotransmission at select cortical synapses

Nat Neurosci. 2011 Apr;14(4):478-86. doi: 10.1038/nn.2757. Epub 2011 Feb 27.


The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are subthreshold, voltage-gated ion channels that are highly expressed in hippocampal and cortical pyramidal cell dendrites, where they are important for regulating synaptic potential integration and plasticity. We found that HCN1 subunits are also localized to the active zone of mature asymmetric synaptic terminals targeting mouse entorhinal cortical layer III pyramidal neurons. HCN channels inhibited glutamate synaptic release by suppressing the activity of low-threshold voltage-gated T-type (Ca(V)3.2) Ca²(+) channels. Consistent with this, electron microscopy revealed colocalization of presynaptic HCN1 and Ca(V)3.2 subunit. This represents a previously unknown mechanism by which HCN channels regulate synaptic strength and thereby neural information processing and network excitability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, T-Type / physiology*
  • Calcium Signaling / genetics
  • Calcium Signaling / physiology
  • Cyclic Nucleotide-Gated Cation Channels / physiology*
  • Entorhinal Cortex / metabolism
  • Entorhinal Cortex / physiology*
  • Entorhinal Cortex / ultrastructure
  • Excitatory Amino Acid Antagonists
  • Glutamates / metabolism
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neural Inhibition / physiology
  • Organ Culture Techniques
  • Potassium Channels / physiology*
  • Presynaptic Terminals / metabolism
  • Presynaptic Terminals / physiology*
  • Presynaptic Terminals / ultrastructure
  • Protein Subunits / physiology
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / physiology*
  • Pyramidal Cells / ultrastructure
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology*


  • CACNA1H protein, human
  • Calcium Channels, T-Type
  • Cyclic Nucleotide-Gated Cation Channels
  • Excitatory Amino Acid Antagonists
  • Glutamates
  • HCN1 protein, human
  • Hcn1 protein, mouse
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Potassium Channels
  • Protein Subunits