Physical parameters of the anesthetic site

Katz, Yehuda; Simon, Sidney A.

doi:10.1016/0005-2736(77)90387-x

Cited by 25 publications

(7 citation statements)

References 21 publications

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“…The results of several experiments have suggested a "bonding mechanism" in which metabolically inert gases bind to specific sites within protein molecules (37,39,64,99,100). However, because there was little evidence to support a role for proteins in the mechanisms of anesthesia, this theory was not popular and the lipid theory was favored.…”

Section: The Protein Theorymentioning

confidence: 96%

Neurochemistry of Pressure‐Induced Nitrogen and Metabolically Inert Gas Narcosis in the Central Nervous System

Rostain

Lavoûte

2016

Comprehensive Physiology

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Gases that are not metabolized by the organism are thus chemically inactive under normal conditions. Such gases include the "noble gases" of the Periodic Table as well as hydrogen and nitrogen. At increasing pressure, nitrogen induces narcosis at 4 absolute atmospheres (ATAs) and more in humans and at 11 ATA and more in rats. Electrophysiological and neuropharmacological studies suggest that the striatum is a target of nitrogen narcosis. Glutamate and dopamine release from the striatum in rats are decreased by exposure to nitrogen at a pressure of 31 ATA (75% of the anesthetic threshold). Striatal dopamine levels decrease during exposure to compressed argon, an inert gas more narcotic than nitrogen, or to nitrous oxide, an anesthetic gas. Inversely, striatal dopamine levels increase during exposure to compressed helium, an inert gas with a very low narcotic potency. Exposure to nitrogen at high pressure does not change N-methyl-d-aspartate (NMDA) glutamate receptor activities in Substantia Nigra compacta and striatum but enhances gama amino butyric acidA (GABAA) receptor activities in Substantia Nigra compacta. The decrease in striatal dopamine levels in response to hyperbaric nitrogen exposure is suppressed by recurrent exposure to nitrogen narcosis, and dopamine levels increase after four or five exposures. This change, the lack of improvement of motor disturbances, the desensitization of GABAA receptors on dopamine cells during recurrent exposures and the long-lasting decrease of glutamate coupled with the higher sensitivity of NMDA receptors, suggest a nitrogen toxicity induced by repetitive exposures to narcosis. These differential changes in different neurotransmitter receptors would support the binding protein theory. © 2016 American Physiological Society. Compr Physiol 6:1579-1590, 2016.

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Section: The Protein Theorymentioning

confidence: 96%

Neurochemistry of Pressure‐Induced Nitrogen and Metabolically Inert Gas Narcosis in the Central Nervous System

Rostain

Lavoûte

2016

Comprehensive Physiology

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“…There have been numerous suggestions over the years, accounting for all of the major components and/or phases within the membrane, for example, lipid [for references see (3 )], protein (59)(60)(61), lipoprotein (62), and cellular water (63,64). Hydrophobic or nonaqueous sites have been given preference (65); however, the possibility exists that more than one region is involved (66,67). The many attempts to define the molecular site of action of anesthetics form the basis of many of the early physical theories of anesthesia.…”

Section: Intramembrane Locationmentioning

confidence: 99%

Physical Mechanisms of Anesthesia

Roth¹

1979

Annu. Rev. Pharmacol. Toxicol.

123

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“…83 This point was reviewed by Katz and Simon in their analysis of the anaesthetic potency of the noble gases. 35 A new point of motivation for the molecular modelling of anaesthetic binding is that the goal of an agent that rapidly reverses anaesthetic or alcohol intoxication may be a reality. In a recent publication, Beckstead and co-workers 5 have carefully selected a mutant glycine receptor that was insensitive to the enhancing effects of ethanol but remained sensitive to en¯urane, toluene and chloroform.…”

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confidence: 99%

Molecular modelling of specific and non-specific anaesthetic interactions

Trudell

Bertaccini²

2002

British Journal of Anaesthesia

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There has been rapid progress in molecular modelling in recent years. The convergence of improved software for molecular mechanics and dynamics, techniques for chimeric substitution and site-directed mutations, and the first x-ray structures of transmembrane ion channels have made it possible to build and test models of anaesthetic binding sites. These models have served as guides for site-directed mutagenesis and as starting points for understanding the molecular dynamics of anaesthetic-site interactions. Ligand-gated ion channels are targets for inhaled anaesthetics and alcohols in the central nervous system. The inhibitory strychnine-sensitive glycine and gamma-aminobutyric acid type A receptors are positively modulated by anaesthetics and alcohols; site-directed mutagenesis techniques have identified amino acid residues important for the action of volatile anaesthetics and alcohols in these receptors. Key questions are whether these amino acid mutations form part of alcohol- or anaesthetic-binding sites or if they alter protein stability in a way that allows anaesthetic molecules to act remotely by non-specific mechanisms. It is likely that molecular modelling will play a major role in answering these questions.

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Physical parameters of the anesthetic site

Cited by 25 publications

References 21 publications

Neurochemistry of Pressure‐Induced Nitrogen and Metabolically Inert Gas Narcosis in the Central Nervous System

Neurochemistry of Pressure‐Induced Nitrogen and Metabolically Inert Gas Narcosis in the Central Nervous System

Physical Mechanisms of Anesthesia

Molecular modelling of specific and non-specific anaesthetic interactions

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