A Molecular Mechanism of General Anesthesia

Eyring, Henry; Woodbury, J. Walter; D'Arrigo, Joseph

doi:10.1097/00000542-197305000-00001

Cited by 115 publications

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“…One of the proposed mechanisms for the effect of ethanol on receptors is a change in hydrogen-bonded water (1,2). In the absence of ethanol, at 20°C, an examination of the MI to MII conversion as a function of osmotic stress showed that MII formation results in the net release of 20 Ϯ 1 water molecules.…”

Section: Discussionmentioning

confidence: 99%

“…: 301-594-3608; Fax: 301-594-0035; E-mail: litman@helix.nih.gov. 1 The abbreviations used are: MI, metarhodopsin I; MII, metarhodopsin II; ROS, rod outer segment; DPH, 1,6-diphenyl-1,3,5-hexatriene. …”

mentioning

confidence: 99%

“…One of the proposed modes of action of ethanol on biological macromolecules and membranes involves the replacement of hydrogen-bonded water by ethanol (1,2). Based on the hydrogen bonding capability of both water and ethanol, it is postulated that they compete for hydrogen bonding sites on the surface of lipids and proteins.…”

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Effect of Ethanol and Osmotic Stress on Receptor Conformation

Mitchell

Litman

2000

Journal of Biological Chemistry

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The combined effects of ethanol and osmolytes on both the extent of formation of metarhodopsin II (MII), which binds and activates transducin, and on acyl chain packing were examined in rod outer segment disc membranes. The ethanol-induced increase in MII formation was amplified by the addition of neutral osmolytes. This enhancement was linear with osmolality. At 360 milliosmolal, the osmolality of human plasma, 50 mM ethanol was 2.7 times more potent than at 0 osmolality, demonstrating the importance of water activity in in vitro experiments dealing with ethanol potency. Ethanol disordered acyl chain packing, and increasing osmolality enhanced this acyl chain disordering. Prior osmotic stress data showed a release of 35 ؎ 2 water molecules upon MII formation. Ethanol increases this number to 49 water molecules, suggesting that ethanol replaces 15 additional water molecules upon MII formation. Amplification of ethanol effects on MII formation and acyl chain packing by osmolytes suggests that ethanol increases the equilibrium concentration of MII both by disordering acyl chain packing and by disrupting rhodopsin-water hydrogen bonds, demonstrating a direct effect of ethanol on rhodopsin. At physiologically relevant levels of osmolality and ethanol, about 90% of ethanol's effect is due to disordered acyl chain packing.One of the proposed modes of action of ethanol on biological macromolecules and membranes involves the replacement of hydrogen-bonded water by ethanol (1, 2). Based on the hydrogen bonding capability of both water and ethanol, it is postulated that they compete for hydrogen bonding sites on the surface of lipids and proteins. Thus, this action of ethanol is equally applicable to mechanisms of ethanol action involving both lipid-mediated and direct protein interactions. The general importance of changes in hydration in enzyme activity is widely acknowledged (3, 4), but there is little detailed knowledge regarding how replacement of water by ethanol in specific protein-water hydrogen bonds might alter protein conformational equilibria or function. In addition, the physical properties of the surrounding phospholipid bilayer are known to modulate membrane function. Ethanol-induced changes in phospholipid hydrogen bonding have been observed to change acyl chain packing in pure lipid bilayers (5-7). Thus, the function of integral membrane receptors could be especially susceptible to the disruption of hydrogen-bonded water by ethanol.Thorough examination of the interplay between ethanol and hydration in modulating membrane receptor function requires the ability to separately analyze the effects of ethanol on both protein structure and bilayer physical properties and to be able to correlate the observed changes. Previously, we examined the effects of ethanol (8) and a series of n-alkanols (9) on both the MI 1 -MII conformational equilibrium and acyl chain packing in the surrounding bilayer. In the present work, the effects of ethanol on the MI-MII equilibrium and acyl chain packing are reexamined as a functi...

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Section: Discussionmentioning

confidence: 99%

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Effect of Ethanol and Osmotic Stress on Receptor Conformation

Mitchell

Litman

2000

Journal of Biological Chemistry

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“…Anaesthetic agents are well known to affect cellular metabolism through several pathways (Cohen, 1973;Biebuyck & Lund, 1974;Hallen & Johansson, 1975), as well as to exert effects on cellular membranes (Trudell & Cohen, 1975) and protein conformation (Eyring et al, 1973 (Wunner et al, 1966;Jefferson & Korner,-1969). The role of tryptophan availability in limiting synthesis of lung proteins is controversial (Gacad et al, 1972;Rannels et al, 1979).…”

Section: Discussionmentioning

confidence: 99%

Reversible inhibition of protein synthesis in lung by halothane

Rannels¹,

Christopherson²,

Watkins³

1983

Biochemical Journal

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Alterations in the synthesis and degradation of proteins were investigated in intact lungs exposed to the volatile anaesthetic halothane. In rat lungs perfused in situ with Krebs-Henseleit bicarbonate buffer containing 4.5% (w/v) bovine serum albumin, 5.6 mM-glucose, plasma concentrations of 19 amino acids and 69OpM-EU-14C]-phenylalanine and equilibrated with O2/N2/CO2 (4:15 :1), protein synthesis, calculated based on the specific radioactivity of aminoacyl-tRNA, was inhibited by halothane. The anaesthetic did not affect degradation of lung proteins. The inhibition of protein synthesis was rapid in onset, dose-dependent, and quickly reversible. It did not appear to be associated with overall energy depletion, with non-specific changes in cellular permeability, or with decreased availability synthesis.Halothane and other anaesthetic agents are well known to affect a number of metabolic pathways, including those of oxidative, glycolytic and protein metabolism. Halothane exposure produced a doserelated inhibition of glutamate oxidation by mitochondria isolated from rat liver, as well as an inhibition of oxygen uptake in several tissues

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“…Indeed, anaesthetic agents have been shown to induce a configurational change by combining with the hydrophobic regions of protein molecules. 16 In the present study, of all the volatile anaesthetic agents investigated, maximal depression of chemotactic migration was produced by methoxyflurane, an agent which also has the highest lipid solubility.…”

Section: Discussionmentioning

confidence: 59%