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

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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

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

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