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Propofol inhibits HCN1. 21 / 21
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"We found a good correlation between effects of two other anesthetic drugs on HCN1 subunits and their hypnotic actions in HCN1 knockout mice; etomidate had no effect on HCN1 channels and its ability to evoke a LORR was unaltered in HCN1 knockout mice whereas propofol selectively inhibits HCN1 subunits and we found a significant decrease in sensitivity of HCN1 knockout mice to hypnotic effects of propofol."
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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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"Here, using single-particle cryo-electron microscopy and electrophysiology, we show that propofol inhibits HCN1 by binding to a mechanistic hotspot in a groove between the S5 and S6 transmembrane helices."
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"Propofol inhibited and slowed the activation of recombinant HCN1, HCN2, and HCN4 channels at clinically relevant concentrations, in which the HCN1 current was the most sensitive of the three."
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"This step assures that eventually incoming noise is deselected, and provides an accurate report of the actual tail currents.Cell attached recordings were made with a seal of 30 MΩ to 2 GΩ and lasted for a minimum of 90 s up to 150 s. For recordings measuring intrinsic PC activity without HCN1 current we added HCN1 blocker propofol (100 µM, European Pharmacopoeia Reference Standard, Sigma-Aldrich, Merck KGaA, Darmstadt, Germany) and selective GABA receptor antagonist CGP52432 (50 µM, Sigma-Aldrich) to block the agonistic effects of propofol on GABA receptors [71]."
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"To determine the contribution of HCN1 and compare that to all HCNs, we used the HCN1 blocker propofol, which does not affect HCN2, HCN3, and HCN4 functioning."
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"Propofol also inhibits HCN1 channels and the HCN1 knock-out mice are known to be less sensitive to unconsciousness due to propofol xref ."
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"2,6-di-iso-propyl phenol (propofol) and its non-anesthetic congener, 2,6-di-tert-butyl phenol, inhibit HCN1 channels by stabilizing closed state(s)."
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"If similarly modest suppression of I h is sufficient to dampen excitability in DRG neurons, significant pain relief might be obtainable without the need to completely suppress HCN function.Our demonst[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Propofol analogs, such as the alkylphenol 2,6-di-tert-butylphenol, impede the gating of HCN1 channels without affecting either γ-aminobutyric acid type A (GABA ) or glycine receptors; they are also antihyperalgesic in animal models of neuropathic pain (17), indicating a role for HCN channel inhibition in the analgesic effect of propofol."
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"In this study, we used AziPm because it both mimics propofol’s inhibition of HCN1 activity and is effective at photolabeling the HCN1 channel.Using this approach, we identified a peptide containing the S3 helix of the VSD in which the Y234 residue was labeled with 3 μM AziPm."
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"Last, site-directed mutagenesis of the residues in the binding pocket identified using MD and PAL, coupled with functional measurements, shows that single amino acid substitutions can abrogate the shifts in voltage dependence even at concentrations as high as 100 μM. Collectively, these data indicate that propofol inhibition of HCN1 activation is mediated by a specific binding site in the VSD.While unexpected, it is not without precedent that AziPm labels a residue (Y234) that is one to two helical turns away from the binding pocket predicted by flooding simulations."
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"Here, using single-particle cryo-electron microscopy and electrophysiology, we show that propofol inhibits HCN1 by binding to a mechanistic hotspot in a groove between the S5 and S6 transmembrane helices."
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"This property may be exploited to develop a water-soluble propofol analog that selectively inhibits peripheral HCN1 channels."
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"Propofol also inhibits HCN1 channels and the HCN1 knock-out mice are known to be less sensitive to unconsciousness due to propofol ."
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"Chen and colleagues argue that the case for HCN1 is stronger than the case for NMDA receptors, because the HCN1 knockout has no effect on etomidate sensitivity (but does decrease sensitivity to propofol, which inhibits HCN1), whereas global knockout of the NMDA receptor epsilon1 subunit moderately reduces ketamine sensitivity, but also reduces sensitivity to pentobarbital, propofol, and benzodiazepines, all thought to act primarily via GABA A receptors."
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"We found a good correlation between effects of two other anesthetic drugs on HCN1 subunits and their hypnotic actions in HCN1 knockout mice; etomidate had no effect on HCN1 channels and its ability to evoke a LORR was unaltered in HCN1 knockout mice whereas propofol selectively inhibits HCN1 subunits ( xref ; xref ; xref ) and we found a significant decrease in sensitivity of HCN1 knockout mice to hypnotic effects of propofol."
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"The alkylphenol general anesthetic propofol (2,6-di-iso-propylphenol) selectively inhibits HCN1 channels versus HCN2-HCN4 and exhibits a modest pharmacokinetic preference for the periphery."
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"Propofol can inhibit HCN1 subunit mediated Ih current in mouse cortical pyramidal neurons (Chen et al., 2005)."
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"Propofol inhibits HCN1 pacemaker channels by selective association with the closed states of the membrane embedded channel core."
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"In addition, hypnotic sensitivity to two other intravenous anesthetics in HCN1 knockout mice matched effects on HCN1 channels; propofol selectively inhibited HCN1 channels and propofol sensitivity was diminished in HCN1 knockout mice whereas etomidate had no effect on HCN1 channels and hypnotic sensitivity to etomidate was unaffected by HCN1 gene deletion."
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