Publications
216 results found
Bertaccini EJ, Dickinson R, Trudell JR, et al., 2014, Molecular modeling of a tandem two pore domain potassium channel reveals a putative binding Site for general anesthetics, ACS Chemical Neuroscience, Vol: 5, Pages: 1246-1252, ISSN: 1948-7193
Anesthetics are thought to mediate a portion of their activity via binding to and modulation of potassium channels. In particular, tandem pore potassium channels (K2P) are transmembrane ion channels whose current is modulated by the presence of general anesthetics and whose genetic absence has been shown to confer a level of anesthetic resistance. While the exact molecular structure of all K2P forms remains unknown, significant progress has been made toward understanding their structure and interactions with anesthetics via the methods of molecular modeling, coupled with the recently released higher resolution structures of homologous potassium channels to act as templates. Such models reveal the convergence of amino acid regions that are known to modulate anesthetic activity onto a common three- dimensional cavity that forms a putative anesthetic binding site. The model successfully predicts additional important residues that are also involved in the putative binding site as validated by the results of suggested experimental mutations. Such a model can now be used to further predict other amino acid residues that may be intimately involved in the target-based structure–activity relationships that are necessary for anesthetic binding.
Franks NP, 2014, The unfolding story of how general anesthetics act, The Wondrous Story of Anesthesia, Pages: 597-608, ISBN: 9781461484400
Soon after Morton's 1846 demonstration of ether anesthesia, von Bibra and Harless proposed that ether acted by extracting brain lipids. This was followed by the influential theory of Meyer and Overton who proposed that anesthetics acted by directly perturbing membrane lipids. During the 1970s, evidence accumulated suggesting that this theory was wrong and the idea that anesthetics acted by directly binding to proteins began to take hold. This is now the accepted view and subsequent work focused on which proteins were important. There is now a consensus as to which proteins are important for intravenous anesthetics, but uncertainty still exists for the inhaled agents, although the anatomical target for these anesthetics in producing surgical immobility has been shown to be the spinal cord, rather than the brain.
Baker R, Gent TC, Yang Q, et al., 2014, Altered activity in the central medial thalamus precedes changes in the neocortex during transitions into both sleep and propofol anesthesia, The Journal of Neuroscience, Vol: 34, Pages: 13326-13335, ISSN: 0270-6474
How general anesthetics cause loss of consciousness is unknown. Some evidence points toward effects on the neocortex causing “top-down” inhibition, whereas other findings suggest that these drugs act via subcortical mechanisms, possibly selectively stimulating networks promoting natural sleep. To determine whether some neuronal circuits are affected before others, we used Morlet wavelet analysis to obtain high temporal resolution in the time-varying power spectra of local field potentials recorded simultaneously in discrete brain regions at natural sleep onset and during anesthetic-induced loss of righting reflex in rats. Although we observed changes in the local field potentials that were anesthetic-specific, there were some common changes in high-frequency (20–40 Hz) oscillations (reductions in frequency and increases in power) that could be detected at, or before, sleep onset and anesthetic-induced loss of righting reflex. For propofol and natural sleep, these changes occur first in the thalamus before changes could be detected in the neocortex. With dexmedetomidine, the changes occurred simultaneously in the thalamus and neocortex. In addition, the phase relationships between the low-frequency (1–4 Hz) oscillations in thalamic nuclei and neocortical areas are essentially the same for natural sleep and following dexmedetomidine administration, but a sudden change in phase, attributable to an effect in the central medial thalamus, occurs at the point of dexmedetomidine loss of righting reflex. Our data are consistent with the central medial thalamus acting as a key hub through which general anesthesia and natural sleep are initiated.
Gelegen C, Gent TC, Ferretti V, et al., 2014, Staying awake - a genetic region that hinders α<sub>2</sub> adrenergic receptor agonist-induced sleep, EUROPEAN JOURNAL OF NEUROSCIENCE, Vol: 40, Pages: 2311-2319, ISSN: 0953-816X
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- Citations: 18
Harris K, Armstrong SP, Campos-Pires R, et al., 2013, Neuroprotection against traumatic brain injury by xenon but not argon, is mediated by inhibition at the NMDA receptor glycine site, Anesthesiology, Vol: 119, Pages: 1137-1148, ISSN: 1528-1175
Background. The inert anesthetic gas xenon is neuroprotective in models of brain injury. Weinvestigate the neuroprotective mechanisms of the inert gases xenon, argon, krypton, neon andhelium in an in vitro model of traumatic brain injury.Methods. We use an in vitro model using mouse organotypic hippocampal brain-slices, subjectedto a focal mechanical trauma, with injury quantified by propidium-iodide fluorescence. Patch-clampelectrophysiology is used to investigate the effect of the inert gases on N-methyl-D-aspartate(NMDA)-receptors and TREK-1 channels, two molecular targets likely to play a role inneuroprotection.Results. Xenon(50%) and, to a lesser extent, argon(50%) are neuroprotective against traumaticinjury when applied following injury [xenon 43±1% protection 72hours after injury (N=104); argon30±6% protection (N=44); mean±SEM]. Helium, neon and krypton are devoid of neuroprotectiveeffect. Xenon(50%) prevents development of secondary injury up to 48 hours after trauma.Argon(50%) attenuates secondary injury, but is less effective than xenon [xenon 50±5% reductionin secondary injury 72hours after injury (N=104); argon 34±8% reduction (N=44); mean±SEM].Glycine reverses the neuroprotective effect of xenon, but not argon, consistent with competitiveinhibition at the NMDA receptor glycine-site mediating xenon neuroprotection against traumaticbrain injury. Xenon inhibits NMDA receptors and activates TREK-1 channels, while argon,krypton, neon and helium have no effect on these ion-channels.Conclusions. Xenon neuroprotection against traumatic brain injury can be reversed by elevatingthe glycine concentration, consistent with inhibition at the NMDA-receptor glycine site playing asignificant role in xenon neuroprotection. Argon and xenon do not act via the same mechanism.
Yip GMS, Chen Z-W, Edge CJ, et al., 2013, A propofol binding site on mammalian GABA<sub>A</sub> receptors identified by photolabeling (vol 9, pg 715, 2013), NATURE CHEMICAL BIOLOGY, Vol: 9, ISSN: 1552-4450
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- Citations: 3
Yip GM, Chen ZW, Edge CJ, et al., 2013, A propofol binding site on mammalian GABAA receptors identified by photolabeling, Nature Chemical Biology, Vol: 9, Pages: 715-720, ISSN: 1552-4469
Propofol is the most important intravenous general anesthetic in current clinical use. It acts by potentiating GABAA (γ-aminobutyric acid type A) receptors, but where it binds to this receptor is not known and has been a matter of some debate. We synthesized a new propofol analog photolabeling reagent whose biological activity is very similar to that of propofol. We confirmed that this reagent labeled known propofol binding sites in human serum albumin that have been identified using X-ray crystallography. Using a combination of protiated and deuterated versions of the reagent to label mammalian receptors in intact membranes, we identified a new binding site for propofol in GABAA receptors consisting of both β3 homopentamers and α1β3 heteropentamers. The binding site is located within the β subunit at the interface between the transmembrane domains and the extracellular domain and lies close to known determinants of anesthetic sensitivity in the transmembrane segments TM1 and TM2.
Sheng SP, Lei B, James ML, et al., 2012, Xenon Neuroprotection in Experimental Stroke <i>Interactions with Hypothermia and Intracerebral Hemorrhage</i>, ANESTHESIOLOGY, Vol: 117, Pages: 1262-1275, ISSN: 0003-3022
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- Citations: 52
Zecharia AY, Yu X, Götz T, et al., 2012, GABAergic inhibition of histaminergic neurons regulates active waking but not the sleep-wake switch or propofol-induced loss of consciousness., J Neurosci, Vol: 32, Pages: 13062-13075
The activity of histaminergic neurons in the tuberomammillary nucleus (TMN) of the hypothalamus correlates with an animal's behavioral state and maintains arousal. We examined how GABAergic inputs onto histaminergic neurons regulate this behavior. A prominent hypothesis, the "flip-flop" model, predicts that increased and sustained GABAergic drive onto these cells promotes sleep. Similarly, because of the histaminergic neurons' key hub-like place in the arousal circuitry, it has also been suggested that anesthetics such as propofol induce loss of consciousness by acting primarily at histaminergic neurons. We tested both these hypotheses in mice by genetically removing ionotropic GABA(A) or metabotropic GABA(B) receptors from histidine decarboxylase-expressing neurons. At the cellular level, histaminergic neurons deficient in synaptic GABA(A) receptors were significantly more excitable and were insensitive to the anesthetic propofol. At the behavioral level, EEG profiles were recorded in nontethered mice over 24 h. Surprisingly, GABAergic transmission onto histaminergic neurons had no effect in regulating the natural sleep-wake cycle and, in the case of GABA(A) receptors, for propofol-induced loss of righting reflex. The latter finding makes it unlikely that the histaminergic TMN has a central role in anesthesia. GABA(B) receptors on histaminergic neurons were dispensable for all behaviors examined. Synaptic inhibition of histaminergic cells by GABA(A) receptors, however, was essential for habituation to a novel environment.
Armstrong SP, Banks PJ, McKitrick TJW, et al., 2012, Identification of two mutations (F758W & F758Y) in the NMDA receptor glycine-binding site that prevent competitive inhibition by xenon without affecting glycine binding, Anesthesiology, Vol: 117, Pages: 38-47, ISSN: 1528-1175
BACKGROUND: Xenon is a general anesthetic with neuroprotective properties. Xenon inhibition at the glycine-binding site of the N-Methyl-D-aspartate (NMDA) receptor mediates xenon neuroprotection against ischemic injury in vitro. Here we identify specific amino acids important for xenon binding to the NMDA receptor, with the aim of finding silent mutations that eliminate xenon binding but leave normal receptor function intact.METHODS:Site-directed mutagenesis was used to mutate specific amino-acids in the GluN1 subunit of rat NMDA receptors. Mutant GluN1/GluN2A receptors were expressed in HEK 293 cells and were assessed functionally using patch-clamp electrophysiology. The responses of the mutant receptors to glycine and anesthetics were determined.RESULTS:Mutation of phenylalanine 758 to an aromatic tryptophan or tyrosine left glycine affinity unchanged, but eliminated xenon binding without affecting the binding of sevoflurane or isoflurane.CONCLUSIONS:These findings confirm xenon binds to the glycine site of the GluN1 subunit of the NMDA receptor and indicate that interactions between xenon and the aromatic ring of the phenylalanine 758 residue are important for xenon binding. Our most important finding is that we have identified two mutations, F758W and F758Y, that eliminate xenon binding to the NMDA receptor glycine site without changing the glycine affinity of the receptor or the binding of volatile anesthetics. The identification of these selective mutations will allow knock-in animals to be used to dissect the mechanism(s) of xenon's neuroprotective and anesthetic properties in vivo.
Houston CM, McGee TP, MacKenzie G, et al., 2012, Are Extrasynaptic GABA<sub>A</sub> Receptors Important Targets for Sedative/Hypnotic Drugs?, JOURNAL OF NEUROSCIENCE, Vol: 32, Pages: 3887-3897, ISSN: 0270-6474
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- Citations: 48
Franks NP, Zecharia AY, 2011, Sleep and general anesthesia, CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE, Vol: 58, Pages: 139-148, ISSN: 0832-610X
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- Citations: 70
Dickinson R, Franks NP, 2010, Bench-to-bedside review: molecular pharmacology and clinical use of inert gases in anesthesia and neuroprotection, Critical Care, Vol: 14, ISSN: 1364-8535
In the past decade there has been a resurgence of interest in the clinical use of inert gases. In the present paper we review the use of inert gases as anesthetics and neuroprotectants, with particular attention to the clinical use of xenon. We discuss recent advances in understanding the molecular pharmacology of xenon and we highlight specific pharmacological targets that may mediate its actions as an anesthetic and neuroprotectant. We summarize recent in vitro and in vivo studies on the actions of helium and the other inert gases, and discuss their potential to be used as neuroprotective agents.
Banks P, Franks NP, Dickinson R, 2010, Xenon neuroprotection against hypoxia-ischaemia is mediated by the <i>N</i>-methyl-D-aspartate receptor glycine site, Meeting of the Anaesthetic-Research-Society, Publisher: OXFORD UNIV PRESS, Pages: 526-526, ISSN: 0007-0912
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- Citations: 1
Pang DSJ, Robledo CJ, Carr DR, et al., 2009, An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 106, Pages: 17546-17551, ISSN: 0027-8424
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- Citations: 64
Zecharia AY, Franks NP, 2009, General Anesthesia and Ascending Arousal Pathways, ANESTHESIOLOGY, Vol: 111, Pages: 695-696, ISSN: 0003-3022
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- Citations: 21
Zecharia AY, Nelson LE, Gent TC, et al., 2009, The Involvement of Hypothalamic Sleep Pathways in General Anesthesia: Testing the Hypothesis Using the GABA<sub>A</sub> Receptor β<sub>3</sub>N265M Knock-In Mouse, JOURNAL OF NEUROSCIENCE, Vol: 29, Pages: 2177-2187, ISSN: 0270-6474
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- Citations: 106
Banks P, Franks NP, Dickinson R, 2009, Competitive Inhibition at the Glycine Site of the N-methyl-D-aspartate Receptor Mediates Xenon Neuroprotection Against Hypoxia-Ischemia, Anesthesiology, Vol: in press
Lu J, Nelson LE, Franks N, et al., 2008, Role of endogenous sleep-wake and analgesic systems in anesthesia, JOURNAL OF COMPARATIVE NEUROLOGY, Vol: 508, Pages: 648-662, ISSN: 0021-9967
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- Citations: 164
Franks NP, 2008, General anaesthesia: From molecular targets to neuronal pathways of sleep and arousal, NATURE REVIEWS NEUROSCIENCE, Vol: 9, Pages: 370-386, ISSN: 1471-003X
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- Citations: 895
Coburn M, Maze M, Franks NP, 2008, The neuroprotective effects of xenon and helium in an <i>in vitro</i> model of traumatic brain injury, CRITICAL CARE MEDICINE, Vol: 36, Pages: 588-595, ISSN: 0090-3493
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- Citations: 121
Bright DP, Adham SD, Lemaire LCJM, et al., 2007, Identification of anesthetic binding sites on human serum albumin using a novel etomidate photolabel, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 282, Pages: 12038-12047
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- Citations: 8
Ma DQ, Williamson P, Januszewski A, et al., 2007, Xenon mitigates isoflurane-induced neuronal apoptosis in the developing rodent brain, Anesthesiology, Vol: 106, Pages: 746-753, ISSN: 0003-3022
Bertaccini EJ, Trudell JR, Franks NP, 2007, The common chemical motifs within anesthetic binding sites, ANESTHESIA AND ANALGESIA, Vol: 104, Pages: 318-324, ISSN: 0003-2999
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- Citations: 42
Martin JL, Ma D, Hossain M, et al., 2007, Asynchronous administration of xenon and hypothermia significantly reduces brain infarction in the neonatal rat, BRITISH JOURNAL OF ANAESTHESIA, Vol: 98, Pages: 236-240, ISSN: 0007-0912
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- Citations: 52
Andres-Enguix I, Caley A, Yustos R, et al., 2007, Determinants of the anesthetic sensitivity of two-pore domain acid-sensitive potassium channels: molecular cloning of an anesthetic-activated potassium channelfrom Lymnaea stagnalis, Journal of Biological Chemistry, Vol: 282, Pages: 20977-20990, ISSN: 0021-9258
Dickinson R, Peterson B, Banks P, et al., 2007, Competitive Inhibition at the Glycine Site of the NMDA Receptor by the Anesthetics Xenon and Isoflurane: Evidence from Molecular Modeling and Electrophysiology, Anesthesiology, Vol: 107, Pages: 756-767
Rajakumaraswamy N, Ma D, Hossain M, et al., 2006, Neuroprotective interaction produced by xenon and dexmedetomidine on <i>in vitro</i> and <i>in vivo</i> neuronal injury models, NEUROSCIENCE LETTERS, Vol: 409, Pages: 128-133, ISSN: 0304-3940
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- Citations: 55
Sakamoto S, Nakao S, Masuzawa M, et al., 2006, The differential effects of nitrous oxide and xenon on extracellular dopamine levels in the rat nucleus accumbens: A microdialysis study, ANESTHESIA AND ANALGESIA, Vol: 103, Pages: 1459-1463, ISSN: 0003-2999
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- Citations: 29
Franks NP, Renavides R, Maze M, 2006, Air bubble growth in water - Reply, ANESTHESIOLOGY, Vol: 105, Pages: 1059-1060, ISSN: 0003-3022
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