Role of Ih in the firing pattern of mammalian cold thermoreceptor endings

J Neurophysiol. 2012 Dec;108(11):3009-23. doi: 10.1152/jn.01033.2011. Epub 2012 Sep 5.


Mammalian peripheral cold thermoreceptors respond to cooling of their sensory endings with an increase in firing rate and modification of their discharge pattern. We recently showed that cultured trigeminal cold-sensitive (CS) neurons express a prominent hyperpolarization-activated current (I(h)), mainly carried by HCN1 channels, supporting subthreshold resonance in the soma without participating in the response to acute cooling. However, peripheral pharmacological blockade of I(h), or characterization of HCN1(-/-) mice, reveals a deficit in acute cold detection. Here we investigated the role of I(h) in CS nerve endings, where cold sensory transduction actually takes place. Corneal CS nerve endings in mice show a rhythmic spiking activity at neutral skin temperature that switches to bursting mode when the temperature is lowered. I(h) blockers ZD7288 and ivabradine alter firing patterns of CS nerve endings, lengthening interspike intervals and inducing bursts at neutral skin temperature. We characterized the CS nerve endings from HCN1(-/-) mouse corneas and found that they behave similar to wild type, although with a lower slope in the firing frequency vs. temperature relationship, thus explaining the deficit in cold perception of HCN1(-/-) mice. The firing pattern of nerve endings from HCN1(-/-) mice was also affected by ZD7288, which we attribute to the presence of HCN2 channels in the place of HCN1. Mathematical modeling shows that the firing phenotype of CS nerve endings from HCN1(-/-) mice can be reproduced by replacing HCN1 channels with the slower HCN2 channels rather than by abolishing I(h). We propose that I(h) carried by HCN1 channels helps tune the frequency of the oscillation and the length of bursts underlying regular spiking in cold thermoreceptors, having important implications for neural coding of cold sensation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / genetics
  • Action Potentials / physiology*
  • Animals
  • Benzazepines / pharmacology
  • Cardiovascular Agents / pharmacology
  • Cold Temperature
  • Cornea / innervation
  • Cyclic Nucleotide-Gated Cation Channels / antagonists & inhibitors
  • Cyclic Nucleotide-Gated Cation Channels / genetics*
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels / antagonists & inhibitors
  • Ion Channels / metabolism
  • Ivabradine
  • Mice
  • Models, Neurological
  • Nerve Endings / physiology*
  • Optic Nerve / physiology
  • Potassium Channels / genetics*
  • Pyrimidines / pharmacology
  • Thermoreceptors / physiology*


  • Benzazepines
  • Cardiovascular Agents
  • Cyclic Nucleotide-Gated Cation Channels
  • Hcn1 protein, mouse
  • Hcn2 protein, mouse
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channels
  • Potassium Channels
  • Pyrimidines
  • ICI D2788
  • Ivabradine