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Ketamine inhibits HCN1. 27 / 27
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"Whereas such in vitro results provide a strong correlative argument to implicate NMDA receptors, we find that the same case can be made for HCN1 channels : EC 50 values obtained for ketamine inhibition of HCN1 channels are within a clinically relevant range and HCN1 channels are more potently inhibited by S-(+)-ketamine than racemic ketamine."
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"At these doses, ketamine blocks presynaptic NMDARs and HCN1 channels that promote glutamate release (141)."
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"The narrow therapeutic dose range for ketamine limits its candidate primary brain targets to just a few including NMDARs and perhaps hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (HCN1) and TrkB receptors (138)."
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"However, HCN1 channel inhibition by ketamine shares a number of characteristics with that described for propofol, including HCN1 subunit-selectivity, insensitivity to cAMP and higher apparent affinity for shifts in V (1/2) than for suppression of maximal current."
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"On the contrary, higher doses of Ketamine (50-100mg/kg), inhibits both NMDA receptors and the HCN1 pacemaker channels."
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"Nonetheless, these data argue strongly that ketamine and propofol inhibit HCN1 containing channels and dendritic I h in cortical neurons to mediate enhanced dendritosomatic synaptic integration."
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"Ketamine acts as an NMDA receptor (NMDAR) antagonist and also blocks GABA A receptors as well as HCN1 cation channels."
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"In the forebrain HCN1 is inhibited by ketamine, contributing to the unique profile of this anesthetic and psychotropic drug [10, 11]."
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"Ketamine has been reported to inhibit HCN1 channels [51]."
35768639
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"Ketamine has been reported to inhibit HCN1 channels[51] and HCN1 was reported necessary for ketamine to exert antidepressant-like actions in mice[62]."
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"Ketamine has also been posited to inhibit HCN1 receptors, which mediate the hyperpolarization-activated cation current."
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"In addition, ketamine inhibits the hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (HCN1), a molecular target that is thought to play an important role in generating rhythmic EEG activity and is considered a novel therapeutic target for depressive disorders ."
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"Because ketamine also blocks HCN1 channels and these channels are expressed on pyramidal neuron dendrites where they regulate dendrosomatic charge transfer and temporal synchronization, we examined whether the effects of ketamine are mimicked by an HCN inhibitor."
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"We previously showed that HCN1 channels are inhibited by ketamine and demonstrated that global HCN1 knockout mice are two-fold less sensitive to hypnotic actions of ketamine."
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"We suggest that ketamine inhibition of HCN1 shifts cortical neuron electroresponsive properties to contribute to ketamine induced hypnosis."
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"In our earlier work, we made the unexpected observation that ketamine inhibited recombinant HCN1 channels at clinically relevant concentrations via a decrease in maximal current amplitude and a hyperpolarizing shift in the V1/2 of channel activation 4."
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"Ketamine reduces HCN1 activity to elicit antidepressant effects."
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"Ketamine reduces HCN1 activity and elicit antidepressant-like response effect through HCN channel inhibition or HCN knockout (Chen et al., 2009; Hou et al., 2018; Ku and Han, 2017; Zhang et al., 2016)."
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"Importantly, whereas ketamine increased EPSP temporal summation by ~ 28% (from 1.9 +/- 0.2 to 2.5 +/- 0.2, n = 5, p < 0.05) in HCN1 f/f mice, this effect of ketamine was totally eliminated in pyramidal neurons of CaMKCre : HCN1 f/f mice (from 3.1 +/- 0.2 to 3.2 +/- 0.2, n = 5, P> 0.05)."
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"In this latter respect, we found that ketamine mediated inhibition of HCN1 containing channels in cortical pyramidal neurons enhances dendritosomatic synaptic integration, an effect that would support the synaptically mediated slow cortical rhythms that accompany the hypnotic state induced by ketamine XREF_BIBR - XREF_BIBR, XREF_BIBR."
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"As knowledge of the molecular determinants for ketamine inhibition of HCN1 channels becomes available, it may be possible to develop knock-in mice that express ketamine insensitive mutant HCN1 channels, preferably in more restricted neuronal populations, to even more rigorously define the molecular and neuronal targets for this specific clinical endpoint of ketamine."
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"These data indicate that HCN2 homomeric channels are relatively unaffected by ketamine, but HCN1 containing channels are strongly inhibited by ketamine in either homomeric or heteromeric configurations."
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"Thus, ketamine inhibits HCN1 containing channels at clinically relevant concentrations and with a stereoselectivity similar to that observed for its anesthetic actions."
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"Inhibition of HCN1 channels by ketamine accounts for its antidepressant actions."
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"Ketamine inhibits HCN1 mediated I h currents at an EC 50 of 15 muM [XREF_BIBR] while it blocks NMDAR channels at EC 50 of 9 muM [XREF_BIBR]."
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"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."
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"Here, we show that ketamine is a potent inhibitor of cloned HCN1 containing channels and of I h in cortical pyramidal neurons; concordant with its anesthetic actions, we found that inhibition by ketamine is stereoselective and evident at clinically relevant concentrations."
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