QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, June 15, 2005, 25(24):5803-5814; doi:10.1523/JNEUROSCI.1153-05.2005

This Article Full Text Full Text (PDF) Supplemental data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (20) Citing Articles via Google Scholar Google Scholar Articles by Chen, X. Articles by Bayliss, D. A. Search for Related Content PubMed PubMed Citation Articles by Chen, X. Articles by Bayliss, D. A.

 Previous Article  |  Next Article 

Cellular/Molecular
HCN Subunit-Specific and cAMP-Modulated Effects of Anesthetics on Neuronal Pacemaker Currents

Xiangdong Chen,¹ Jay E. Sirois,² Qiubo Lei,¹ Edmund M. Talley,¹ Carl Lynch, III,² and Douglas A. Bayliss^1,2

Departments of ¹Pharmacology and ²Anesthesiology, University of Virginia, Charlottesville, Virginia 22908

General anesthetics have been a mainstay of surgical practice for more than 150 years, but the mechanisms by which they mediate their important clinical actions remain unclear. Ion channels represent important anesthetic targets, and, although GABA_A receptors have emerged as major contributors to sedative, immobilizing, and hypnotic effects of intravenous anesthetics, a role for those receptors is less certain in the case of inhalational anesthetics. The neuronal hyperpolarization-activated pacemaker current (I_h) is essential for oscillatory and integrative properties in numerous cell types. Here, we show that clinically relevant concentrations of inhalational anesthetics modulate neuronal I_h and the corresponding HCN channels in a subunit-specific and cAMP-dependent manner. Anesthetic inhibition of I_h involves a hyperpolarizing shift in voltage dependence of activation and a decrease in maximal current amplitude; these effects can be ascribed to HCN1 and HCN2 subunits, respectively, and both actions are recapitulated in heteromeric HCN1-HCN2 channels. Mutagenesis and simulations suggest that apparently distinct actions of anesthetics on V_1/2 and amplitude represent different manifestations of a single underlying mechanism (i.e., stabilization of channel closed state), with the predominant action determined by basal inhibition imposed by individual subunit C-terminal domains and relieved by cAMP. These data reveal a molecular basis for multiple actions of anesthetics on neuronal HCN channels, highlight the importance of proximal C terminus in modulation of HCN channel gating by diverse agents, and advance neuronal pacemaker channels as potentially relevant targets for clinical actions of inhaled anesthetics.

Key words: anesthesia; arousal; motoneuron; neuromodulation; pacemaker; thalamus; voltage clamp; cAMP

---

Received Jan 5, 2005; revised May 15, 2005; accepted May 16, 2005.

This article has been cited by other articles:

				T. Kanyshkova, M. Pawlowski, P. Meuth, C. Dube, R. A. Bender, A. L. Brewster, A. Baumann, T. Z. Baram, H.-C. Pape, and T. Budde Postnatal Expression Pattern of HCN Channel Isoforms in Thalamic Neurons: Relationship to Maturation of Thalamocortical Oscillations J. Neurosci., July 8, 2009; 29(27): 8847 - 8857. [Abstract] [Full Text] [PDF]

				M. Biel, C. Wahl-Schott, S. Michalakis, and X. Zong Hyperpolarization-Activated Cation Channels: From Genes to Function Physiol Rev, July 1, 2009; 89(3): 847 - 885. [Abstract] [Full Text] [PDF]

				A. S. Lewis, E. Schwartz, C. Savio Chan, Y. Noam, M. Shin, W. J. Wadman, D. James Surmeier, T. Z. Baram, R. L. Macdonald, and D. M. Chetkovich Alternatively Spliced Isoforms of TRIP8b Differentially Control h Channel Trafficking and Function J. Neurosci., May 13, 2009; 29(19): 6250 - 6265. [Abstract] [Full Text] [PDF]

				P. Orio, R. Madrid, E. de la Peña, A.és Parra, Víc. Meseguer, D. A. Bayliss, C. Belmonte, and Fél. Viana Characteristics and physiological role of hyperpolarization activated currents in mouse cold thermoreceptors J. Physiol., May 1, 2009; 587(9): 1961 - 1976. [Abstract] [Full Text] [PDF]

				X. Chen, S. Shu, and D. A. Bayliss HCN1 Channel Subunits Are a Molecular Substrate for Hypnotic Actions of Ketamine J. Neurosci., January 21, 2009; 29(3): 600 - 609. [Abstract] [Full Text] [PDF]

				X. Chen, S. Shu, D. P. Kennedy, S. C. Willcox, and D. A. Bayliss Subunit-Specific Effects of Isoflurane on Neuronal Ih in HCN1 Knockout Mice J Neurophysiol, January 1, 2009; 101(1): 129 - 140. [Abstract] [Full Text] [PDF]

				A. K. Lyashchenko, K. J. Redd, J. Yang, and G. R. Tibbs Propofol inhibits HCN1 pacemaker channels by selective association with the closed states of the membrane embedded channel core J. Physiol., August 15, 2007; 583(1): 37 - 56. [Abstract] [Full Text] [PDF]

				S. K. Jankelowitz, J. Howells, and D. Burke Plasticity of inwardly rectifying conductances following a corticospinal lesion in human subjects J. Physiol., June 15, 2007; 581(3): 927 - 940. [Abstract] [Full Text] [PDF]

				S. Chen, J. Wang, L. Zhou, M. S. George, and S. A. Siegelbaum Voltage Sensor Movement and cAMP Binding Allosterically Regulate an Inherently Voltage-independent Closed-Open Transition in HCN Channels J. Gen. Physiol., January 29, 2007; 129(2): 175 - 188. [Abstract] [Full Text] [PDF]

				X. Chen, S. Shu, and D. A. Bayliss Suppression of Ih Contributes to Propofol-Induced Inhibition of Mouse Cortical Pyramidal Neurons J Neurophysiol, December 1, 2005; 94(6): 3872 - 3883. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help