title: Functional impact of the hyperpolarization-activated current on the excitability of myelinated A-type vagal afferent neurons in the rat.
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.
authors.affiliation: Department of Pharmacology, Harbin Medical University, Harbin, China.
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Zhou
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Sun
authors.forename: Zhen-Hong
authors.initials: ZH
authors.lastname: Liu
authors.forename: Guixue
authors.initials: G
authors.lastname: Bu
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Pang
authors.forename: Shi-Chao
authors.initials: SC
authors.lastname: Sun
authors.forename: Guo-Fen
authors.initials: GF
authors.lastname: Qiao
authors.forename: Bai-Yan
authors.initials: BY
authors.lastname: Li
authors.forename: John H
authors.initials: JH
authors.lastname: Schild
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002469:Cell Separation; D002478:Cells, Cultured; D002586:Cesium / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000187:drug effects* / Q000378:metabolism*; D004594:Electrophysiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009413:Nerve Fibers, Myelinated / Q000502:physiology*; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D009475:Neurons, Afferent / Q000502:physiology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014630:Vagus Nerve / Q000502:physiology*
chemical_list: D002712:Chlorides; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D002586:Cesium; C028019:cesium chloride
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