Error message

No crossref credentials set for jneuro

HCN1 Channel Subunits Are a Molecular Substrate for Hypnotic Actions of Ketamine

J. Neurosci., 21 January 2009
Vol. 29, Issue 3, p. 600-609
DOI: 10.1523/JNEUROSCI.3481-08.2009

HCN1 Channel Subunits Are a Molecular Substrate for Hypnotic Actions of Ketamine

  1. Xiangdong Chen 1 ,
  2. Shaofang Shu 1 , and
  3. Douglas A. Bayliss 1 , 2
  1. 1Departments of Pharmacology and
  2. 2Anesthesiology, University of Virginia, Charlottesville, Virginia 22908
  1. Correspondence should be addressed to Douglas A. Bayliss, Department of Pharmacology, University of Virginia Health System, P.O. Box 800735, 1300 Jefferson Park Avenue, Charlottesville, VA 22908-0735. dab3y{at}virginia.edu

Abstract

Ketamine has important anesthetic, analgesic, and psychotropic actions. It is widely believed that NMDA receptor inhibition accounts for ketamine actions, but there remains a dearth of behavioral evidence to support this hypothesis. Here, we present an alternative, behaviorally relevant molecular substrate for anesthetic effects of ketamine: the HCN1 pacemaker channels that underlie a neuronal hyperpolarization-activated cationic current (I h). Ketamine caused subunit-specific inhibition of recombinant HCN1-containing channels and neuronal I h at clinically relevant concentrations; the channels were more potently inhibited by S-(+)-ketamine than racemic ketamine, consistent with anesthetic actions of the compounds. In cortical pyramidal neurons from wild-type, but not HCN1 knock-out mice, ketamine induced membrane hyperpolarization and enhanced dendritosomatic synaptic coupling; both effects are known to promote cortical synchronization and support slow cortical rhythms, like those accompanying anesthetic-induced hypnosis. Accordingly, we found that the potency for ketamine to provoke a loss-of-righting reflex, a behavioral correlate of hypnosis, was strongly reduced in HCN1 knock-out mice. In addition, hypnotic sensitivity to two other intravenous anesthetics in HCN1 knock-out mice matched effects on HCN1 channels; propofol selectively inhibited HCN1 channels and propofol sensitivity was diminished in HCN1 knock-out mice, whereas etomidate had no effect on HCN1 channels and hypnotic sensitivity to etomidate was unaffected by HCN1 gene deletion. These data advance HCN1 channels as a novel molecular target for ketamine, provide a plausible neuronal mechanism for enhanced cortical synchronization during anesthetic-induced hypnosis and suggest that HCN1 channels might contribute to other unexplained actions of ketamine.

  • anesthesia
  • I h
  • hyperpolarization-activated current
  • propofol
  • cortical pyramidal neurons
  • sleep

Citation:

X. Chen, S. Shu, and D. A. Bayliss, HCN1 Channel Subunits Are a Molecular Substrate for Hypnotic Actions of Ketamine. J. Neurosci. 29, 600-609 (2009).

Effect of Memantine on Cough Reflex Sensitivity: Translational Studies in Guinea Pigs and Humans
P. V. Dicpinigaitis, B. J. Canning, R. Garner, and B. Paterson
J. Pharmacol. Exp. Ther. 352, 448-454 (1 March 2015)

The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study: protocol for an international multicentre randomised controlled trial
M. S. Avidan, B. A. Fritz, H. R. Maybrier, M. R. Muench, K. E. Escallier, Y. Chen, A. Ben Abdallah, R. A. Veselis, J. A. Hudetz, P. S. Pagel et al.
BMJ Open 4, e005651-e005651 (1 October 2014)

Elevation in Type I Interferons Inhibits HCN1 and Slows Cortical Neuronal Oscillations
K. Stadler, C. Bierwirth, L. Stoenica, A. Battefeld, O. Reetz, E. Mix, S. Schuchmann, T. Velmans, K. Rosenberger, A. U. Brauer et al.
Cereb Cortex 24, 199-210 (1 January 2014)

Prefrontal Cortex HCN1 Channels Enable Intrinsic Persistent Neural Firing and Executive Memory Function
S. J. Thuault, G. Malleret, C. M. Constantinople, R. Nicholls, I. Chen, J. Zhu, A. Panteleyev, S. Vronskaya, M. F. Nolan, R. Bruno et al.
J. Neurosci. 33, 13583-13599 (21 August 2013)

A randomized controlled trial of intranasal ketamine in migraine with prolonged aura
S. K. Afridi, N. J. Giffin, H. Kaube, and P. J. Goadsby
Neurology 80, 642-647 (12 February 2013)

HCN1 Channels: A New Therapeutic Target for Depressive Disorders?
M. M. Shah, N. J. Giffin, H. Kaube, and P. J. Goadsby
Sci Signal 5, pe44-pe44 (2 October 2012)

Flash Responses of Mouse Rod Photoreceptors in the Isolated Retina and Corneal Electroretinogram: Comparison of Gain and Kinetics
H. Heikkinen, F. Vinberg, M. Pitkanen, B. Kommonen, and A. Koskelainen
IOVS 53, 5653-5664 (17 August 2012)

Microglial Ca2+-Activated K+ Channels Are Possible Molecular Targets for the Analgesic Effects of S-Ketamine on Neuropathic Pain
Y. Hayashi, K. Kawaji, L. Sun, X. Zhang, K. Koyano, T. Yokoyama, S. Kohsaka, K. Inoue, and H. Nakanishi
J. Neurosci. 31, 17370-17382 (30 November 2011)

Properties of Slow Oscillation during Slow-Wave Sleep and Anesthesia in Cats
S. Chauvette, S. Crochet, M. Volgushev, and I. Timofeev
J. Neurosci. 31, 14998-15008 (19 October 2011)

Local Anesthetic Inhibits Hyperpolarization-Activated Cationic Currents
Q.-t. Meng, Z.-y. Xia, J. Liu, D. A. Bayliss, and X. Chen
Mol. Pharmacol. 79, 866-873 (1 May 2011)

Potentiating Action of Propofol at GABAA Receptors of Retinal Bipolar Cells
L. Yue, A. Xie, K. S. Bruzik, B. Frolund, H. Qian, and D. R. Pepperberg
IOVS 52, 2497-2509 (16 April 2011)

Glutamate Receptor Subtypes Mediating Synaptic Activation of Prefrontal Cortex Neurons: Relevance for Schizophrenia
D. C. Rotaru, H. Yoshino, D. A. Lewis, G. B. Ermentrout, and G. Gonzalez-Burgos
J. Neurosci. 31, 142-156 (5 January 2011)

Homeostatic Regulation of Synaptic Excitability: Tonic GABAA Receptor Currents Replace Ih in Cortical Pyramidal Neurons of HCN1 Knock-Out Mice
X. Chen, S. Shu, L. C. Schwartz, C. Sun, J. Kapur, and D. A. Bayliss
J. Neurosci. 30, 2611-2622 (17 February 2010)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882