Functional impact of the hyperpolarization-activated current on the excitability of myelinated A-type vagal afferent neurons in the rat

Clin Exp Pharmacol Physiol. 2010 Aug;37(8):852-61. doi: 10.1111/j.1440-1681.2010.05396.x. Epub 2010 Apr 26.

Abstract

1. The hyperpolarization-induced, cation-selective current I(h) is widely observed in peripheral sensory neurons of the vagal and dorsal root ganglia, but the peak magnitude and voltage- and time-dependent properties of this current vary widely across afferent fibre type. 2. Using patch clamp investigations of rat isolated vagal ganglion neurons (VGN) identified as myelinated A-type afferents, we established a compendium of functional correlates between changes in membrane potential and the dynamic discharge properties of these sensory neurons as a result of the controlled recruitment of I(h) using the current clamp technique. 3. Two robust responses were observed in response to hyperpolarizing step currents: (i) upon initiation of the negative step current, there was a rapid hyperpolarization of membrane potential followed by a depolarizing voltage sag (DVS) towards a plateau in membrane potential as a result of steady state recruitment of I(h); and (ii) upon termination of the negative step current, there was a rapid return to the pretest resting membrane potential that often led to spontaneous action potential discharge. These data were strongly correlated (r(2) > 0.9) with a broad compendium of dynamic discharge characteristics in these A-type VGN. 4. In response to depolarizing step currents of increasing magnitude, the discharge frequency of the A-type VGN responded with increases in the rate of sustained repetitive discharge. Upon termination of the depolarizing step current, there was a post-excitatory membrane hyperpolarization of a magnitude that was strongly correlated with action potential discharge rate (r(2) > 0.9). 5. Application of the selective hyperpolarization-activated cyclic nucleotide gated (HCN) channel blockers ZD7288 (10 micromol/L) or CsCl (1.0 mmol/L) abolished I(h) and all of the aforementioned functional correlates. In addition to reducing the excitability of the A-type VGN to step depolarizing currents. 6. Because there is increasing evidence that the HCN channel current may represent a valid target for pharmacological intervention, the quantitative relationships described in the present study could potentially help guide the molecular and/or chemical modification of HCN channel gating properties to effect a particular outcome in VGN discharge properties, ideally well beyond merely selective blockade of a particular HCN channel subtype.

Publication types

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

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Cell Separation
  • Cells, Cultured
  • Cesium / pharmacology
  • Chlorides / pharmacology
  • Cyclic Nucleotide-Gated Cation Channels / drug effects*
  • Cyclic Nucleotide-Gated Cation Channels / metabolism*
  • Electrophysiology
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Ion Channel Gating / drug effects
  • Male
  • Membrane Potentials / physiology
  • Nerve Fibers, Myelinated / physiology*
  • Nerve Fibers, Unmyelinated / physiology
  • Neurons, Afferent / physiology*
  • Patch-Clamp Techniques
  • Potassium Channels / drug effects*
  • Potassium Channels / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Vagus Nerve / physiology*

Substances

  • Chlorides
  • Cyclic Nucleotide-Gated Cation Channels
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Potassium Channels
  • Cesium
  • cesium chloride