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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Available from: Douglas A Bayliss, Oct 06, 2015
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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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    ABSTRACT: Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents, and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts.
    Frontiers in Pharmacology 07/2014; 5:177. DOI:10.3389/fphar.2014.00177 · 3.80 Impact Factor
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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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    ABSTRACT: Recent studies of propofol-induced unconsciousness have identified characteristic properties of electroencephalographic alpha rhythms that may be mediated by drug activity at γ-aminobutyric acid (GABA) receptors in the thalamus. However, the effect of ketamine (a primarily non-GABAergic anesthetic drug) on alpha oscillations has not been systematically evaluated. We analyzed the electroencephalogram of 28 surgical patients during consciousness and ketamine-induced unconsciousness with a focus on frontal power, frontal cross-frequency coupling, frontal-parietal functional connectivity (measured by coherence and phase lag index), and frontal-to-parietal directional connectivity (measured by directed phase lag index) in the alpha bandwidth. Unlike past studies of propofol, ketamine-induced unconsciousness was not associated with increases in the power of frontal alpha rhythms, characteristic cross-frequency coupling patterns of frontal alpha power and slow-oscillation phase, or decreases in coherence in the alpha bandwidth. Like past studies of propofol using undirected and directed phase lag index, ketamine reduced frontal-parietal (functional) and frontal-to-parietal (directional) connectivity in the alpha bandwidth. These results suggest that directional connectivity changes in the alpha bandwidth may be state-related markers of unconsciousness induced by both GABAergic and non-GABAergic anesthetics.
    Frontiers in Systems Neuroscience 07/2014; 8:114. DOI:10.3389/fnsys.2014.00114
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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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    ABSTRACT: The distribution of ion channels in neurons regulates neuronal activity and proper formation of neuronal networks during neuronal development. One of the channels is the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel constituting the molecular substrate of hyperpolarization-activated current (Ih ). Our previous study implied a role for the fastest activating subunit HCN1 in the generation of Ih in rat neonatal cortical plate neurons. To better understand the impact of HCN1 in early neocortical development we here performed biochemical analysis and whole-cell recordings in neonatal cortical plate and juvenile layer 5 somatosensory neurons of HCN1(-/-) and control HCN1(+/+) mice. Western Blot analysis revealed that HCN1 protein expression in neonatal cortical plate tissue of HCN(+/+) mice amounted to only 3% of the HCN1 in young adult cortex and suggested that in HCN1(-/-) mice other isoforms (particularly HCN4) might be compensatory up-regulated. At the first day after birth, functional ablation of the HCN1 subunit did not affect the proportion of Ih expressing pyramidal cortical plate neurons. Although the contribution of individual subunit proteins remains open, the lack of HCN1 markedly slowed the current activation and deactivation in individual Ih expressing neurons. However, it did not impair maximal amplitude/density, voltage dependence of activation and cAMP sensitivity. In conclusion, our data imply that, although expression is relatively low, HCN1 contributes substantially to Ih properties in individual cortical plate neurons. These properties are significantly changed in HCN1(-/-) , either due to the lack of HCN1 itself or due to compensatory mechanisms. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013.
    Developmental Neurobiology 10/2013; 73(10). DOI:10.1002/dneu.22104 · 3.37 Impact Factor
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