Functional impact of the hyperpolarization-activated current on the excitability of myelinated A-type vagal afferent neurons in the rat.
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.
Zhou
Yu-Hong
YH
Department of Pharmacology, Harbin Medical University, Harbin, China.
Sun
Li-Hua
LH
Liu
Zhen-Hong
ZH
Bu
Guixue
G
Pang
Xiao-Ping
XP
Sun
Shi-Chao
SC
Qiao
Guo-Fen
GF
Li
Bai-Yan
BY
Schild
John H
JH
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*
D002712:Chlorides; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D002586:Cesium; C028019:cesium chloride
Pharmacol Rev. 2005 Dec;57(4):455-62
16382102
J Neurosci Methods. 2002 Apr 15;115(2):157-67
11992667
J Physiol. 2008 Dec 15;586(24):5911-29
18936078
J Neurophysiol. 1997 Dec;78(6):3198-209
9405539
Eur J Neurosci. 2006 Oct;24(7):1976-86
17040479
J Physiol. 2004 Apr 15;556(Pt 2):337-45
14754998
Reg Anesth Pain Med. 2005 May-Jun;30(3):243-8
15898027
J Neurosci Res. 2004 Jun 1;76(5):713-22
15139030
J Physiol. 2009 Dec 15;587(Pt 24):5879-97
19884321
Curr Pharm Des. 2009;15(18):2149-68
19519450
Am J Physiol Regul Integr Comp Physiol. 2009 Jul;297(1):R52-9
19403861
Am J Physiol Regul Integr Comp Physiol. 2008 Oct;295(4):R1301-10
18685060
J Neurosci. 2004 Mar 31;24(13):3335-43
15056713
Nature. 1998 Jun 11;393(6685):587-91
9634236
Brain Res. 2006 Jun 22;1096(1):40-52
16765328
J Neurophysiol. 1994 Jun;71(6):2338-58
7523613
Neuroscience. 2010 Jan 13;165(1):39-52
19815055
J Physiol. 1999 Jan 1;514 ( Pt 1):125-38
9831721
Neuroscience. 2001;106(4):689-98
11682156
Nature. 2003 Sep 11;425(6954):200-5
12968185
Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17991-6
17101981
Brain Res. 2008 May 1;1207:102-10
18377879
Cardiovasc Res. 2008 Sep 1;79(4):715-21
18524809
Pain. 2008 Jul 31;137(3):495-506
18179873
EMBO J. 2003 Jan 15;22(2):216-24
12514127
J Neurophysiol. 2008 Aug;100(2):576-86
18509074
J Neurosci Methods. 2007 Aug 15;164(1):75-85
17512602
Am J Physiol Cell Physiol. 2009 Sep;297(3):C654-64
19570896
J Pain. 2005 Jul;6(7):417-24
15993819
Trends Neurosci. 2003 Oct;26(10):550-4
14522148
J Gen Physiol. 2008 Mar;131(3):227-43
18270171
Am J Physiol Cell Physiol. 2008 Aug;295(2):C557-65
18579800
Sheng Li Xue Bao. 2008 Oct 25;60(5):579-80
18958363
News Physiol Sci. 2002 Feb;17:32-7
11821534