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

Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2009; 29(3):600-9. DOI: 10.1523/JNEUROSCI.3481-08.2009
Source: PubMed


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.

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    • "In addition, ketamine targets NDUSF4, an 18 kDa subunit of mitochondrial complex I (Quintana et al., 2012). Ketamine also inhibits the hyperpolarization-activated cation current channel (HCN1), which results in extended hyperpolarization of neurons (Chen et al., 2009). HCN1 knockout mice show a significant decrease in sensitivity to ketamine (Chen et al., 2009). "
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    • "At the molecular level, the γ-aminobutyric acid (GABA)A receptor is not the primary target for ketamine, unlike many drugs used for the induction and maintenance of general anesthesia. Rather, ketamine is thought to act by antagonizing glutamatergic N-methyl-D-aspartate (NMDA) receptors (like the related anesthetics nitrous oxide and xenon) and/or hyperpolarization-activated cyclic-nucleotide gated (HCN)1 channels (Yamamura et al., 1990; Chen et al., 2009; Zhou et al., 2013). At the neurochemical level, ketamine is unique because it increases cortical acetylcholine levels and appears to depend on noradrenergic signaling for its effects, in contrast to a number of GABAergic anesthetics (Kikuchi et al., 1997; Kushikata et al., 2011). "
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    • "In conclusion, the actual contribution of the HCN1 subunit to the I h at P0 remained uncertain. Although in the last years preferential but partial HCN1 inhibitors such as ketamine (Chen et al., 2009) or type I interferons (Stadler et al., 2012) were found, to this day agents providing a potent block of HCN channel subunits are not available. Therefore, we here investigated the contribution of the HCN1 subunit in the generation of I h by analyzing electrophysiological and biochemical differences between HCN1 1/1 and HCN1 2/2 mice (Nolan et al., 2003). "
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