Journal ArticleDOI
General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit.
Rachel Jurd,Margarete Arras,Sachar Lambert,Berthold Drexler,Roberta Siegwart,Florence Crestani,Michael Zaugg,Kaspar E. Vogt,Birgit Ledermann,Bernd Antkowiak,Uwe Rudolph +10 more
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TLDR
It is demonstrated that a single molecular target, and indeed a specific residue (N265) located within the GABAA receptor β3 subunit, is a major determinant of behavioral responses evoked by the intravenous anesthetics etomidate and propofol, whereas volatile anesthetic appear to act via a broader spectrum of molecular targets.Abstract:
General anesthetics are widely used in clinical practice. On the molecular level, these compounds have been shown to modulate the activity of various neuronal ion channels. However, the functional relevance of identified sites in mediating essential components of the general anesthetic state, such as immobility and hypnosis, is still unknown. Using gene-targeting technology, we generated mice harboring a subtle point mutation (N265M) in the second transmembrane region of the beta3 subunit of the GABA(A) receptor. In these mice, the suppression of noxious-evoked movements in response to the intravenous anesthetics etomidate and propofol is completely abolished, while only slightly decreased with the volatile anesthetics enflurane and halothane. beta3(N265M) mice also display a profound reduction in the loss of righting reflex duration in response to intravenous but not volatile anesthetics. In addition, electrophysiological recordings revealed that anesthetic agents were significantly less effective in enhancing GABA(A) receptor-mediated currents, and in decreasing spontaneous action potential firing in cortical brain slices derived from mutant mice. Taken together, our results demonstrate that a single molecular target, and indeed a specific residue (N265) located within the GABA(A) receptor beta3 subunit, is a major determinant of behavioral responses evoked by the intravenous anesthetics etomidate and propofol, whereas volatile anesthetics appear to act via a broader spectrum of molecular targets.read more
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Journal ArticleDOI
General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal
TL;DR: Comparisons with the features of natural sleep are helping to understand how anaesthetics work and the neuronal pathways that they affect, and suggests that the thalamus and the neurons that regulate its activity are the key to understanding how anaesthetic-induced loss of consciousness is understood.
Journal ArticleDOI
International Union of Pharmacology. LXX. Subtypes of γ-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update
Richard W. Olsen,Werner Sieghart +1 more
TL;DR: This review attempts to summarize experimental evidence on the existence of defined native GABAA receptor subtypes and to produce a list of receptors that actually seem to exist according to current knowledge, and proposes several criteria, which can be applied to all the members of the LGIC superfamily, for including a receptor subtype on a lists of native hetero-oligomeric subtypes.
Journal ArticleDOI
GABAA receptors: Subtypes provide diversity of function and pharmacology
Richard W. Olsen,Werner Sieghart +1 more
TL;DR: This mini-review attempts to update experimental evidence on the existence of GABA(A) receptor pharmacological subtypes and to produce a list of those native receptors that exist and proposes several criteria for including a receptor hetero-oligomeric subtype candidate on a lists of native subtypes, and a working GABA( A) receptor list.
Journal ArticleDOI
Molecular and neuronal substrates for general anaesthetics.
Uwe Rudolph,Bernd Antkowiak +1 more
TL;DR: The neuronal systems that are thought to be involved in mediating clinically relevant actions of general anaesthetics are described and how the function of individual drug targets, in particular GABAA-receptor subtypes, can be revealed by genetic studies in vivo is discussed.
Journal ArticleDOI
Mechanisms of actions of inhaled anesthetics.
TL;DR: “Suffering so great as I underwent cannot be expressed in words, but the blank whirlwind of emotion, the horror of great darkness, and the sense of desertion by God and man, which swept through my mind, and overwhelmed my heart, I can never forget.
References
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Journal ArticleDOI
Molecular and cellular mechanisms of general anaesthesia
TL;DR: It is now clear that anaesthetics act directly on proteins rather than on lipids, with potentiation of postsynaptic inhibitory channel activity best fitting the pharmacological profile observed in general anaesthesia.
Journal Article
International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.
Eric A. Barnard,P. Skolnick,Richard W. Olsen,H. Mohler,W. Sieghart,G. Biggio,C. Braestrup,A. N. Bateson,S. Z. Langer +8 more
TL;DR: This article does not aim to review in detail the properties of γ-aminobutyric acidA(GABAA)breceptors, but in this same journal, a review of the binding properties and pharmacology of these receptors has been published.
Journal ArticleDOI
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
S. John Mihic,S. John Mihic,Qing Ye,Marilee J. Wick,Marilee J. Wick,Vladimir V. Koltchine,Matthew D. Krasowski,Suzanne E. Finn,Maria Paola Mascia,C. Fernando Valenzuela,Kirsten K. Hanson,Eric P. Greenblatt,R. Adron Harris,R. Adron Harris,Neil L. Harrison +14 more
TL;DR: Observations support the idea that anaesthetics exert a specific effect on these ion-channel proteins, and allow for the future testing of specific hypotheses of the action of anaesthetic action.
Journal ArticleDOI
Benzodiazepine actions mediated by specific γ-aminobutyric acid A receptor subtypes
Uwe Rudolph,Florence Crestani,Dietmar Benke,Ina Brünig,Jack A. Benson,Jean-Marc Fritschy,James R. Martin,Horst Bluethmann,Hanns Möhler +8 more
TL;DR: In this article, a histidine-to-arginine point mutation at position 101 of the murine α1-subunit gene was found to render α-type GABAA receptors insensitive to allosteric modulation by benzodiazepine-site ligands, whilst regulation by the physiological neurotransmitter γ-aminobutyric acid is preserved.
Journal ArticleDOI
Efficient in vivo manipulation of mouse genomic sequences at the zygote stage
Merja Lakso,José G. Pichel,James R Gorman,Brian C. Sauer,Yo Okamoto,Eric Lee,Frederick W. Alt,Heiner Westphal +7 more
TL;DR: A transgenic mouse line carrying the cre transgene under the control of the adenovirus EIIa promoter that targets expression of the Cre recombinase to the early mouse embryo is described and loxP-flanked DNA sequences are efficiently deleted.