Interactions of Inert Anesthetic Gases With Proteins

Featherstone, R. M.; Muehlbaecher, C. A.; Debon, F. L.; Forsaith, Janet

doi:10.1097/00000542-196111000-00018

Cited by 49 publications

(12 citation statements)

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“…It is the anesthetic-protein interactions that allow a higher anesthetic concentration near the interface, leading to an apparent higher solubility in protein solution than that in water. 44-45 The adsorption of anesthetics was also observed on a smaller globular protein, HEWL (Fig. S1).…”

Section: Resultsmentioning

confidence: 89%

Critical Role of Water in the Binding of Volatile Anesthetics to Proteins

Wang

Kleinhammes

Tang³

et al. 2013

J. Phys. Chem. B

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Numerous small molecules exhibit drug-like properties by low-affinity binding to proteins. Such binding is known to be influenced by water, the detailed picture of which, however, remains unclear. One particular example is the controversial role of water in the binding of general anesthetics to proteins as an essential step in general anesthesia. Here we demonstrate that a critical amount of hydration water is a prerequisite for anesthetic-protein binding. Using nuclear magnetic resonance, the concurrent adsorption of hydration water and bound anesthetics on model proteins are simultaneously measured. Halothane binding on proteins can only take place after protein hydration reaches a threshold hydration level of ~0.31 gram of water per gram of proteins at the relative water vapor pressure of ~0.95. Similar dependence on hydration is also observed for several other proteins. The ratio of anesthetic partial pressures at which two different anesthetics reach the same fractional load is correlated with the anesthetic potency. The binding of nonimmobilizers, which are structurally similar to known anesthetics but unable to produce anesthesia, does not occur even after the proteins are fully hydrated. Our results provide the first unambiguous experimental evidence that water is absolutely required to enable anesthetic-protein interactions, shedding new light on the general mechanism of molecular recognition and binding.

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Section: Resultsmentioning

confidence: 89%

Critical Role of Water in the Binding of Volatile Anesthetics to Proteins

Wang

Kleinhammes

Tang³

et al. 2013

J. Phys. Chem. B

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“…This relationship implies, surprisingly in light of their diverse structures, that, after they have arrived at their destination, all GAs are equally effective. Accordingly, because GAs dissolve in the oily core of the lipid bilayer, they were long thought to perturb the featureless dielectric in which ion channels, receptors, and pumps are embedded (18)(19)(20)(21)(22)(23)(24), although an action on proteins could never be ruled out (25,26).…”

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confidence: 99%

Electron spin changes during general anesthesia in Drosophila

Turin

Skoulakis

Horsfield

2014

Proc. Natl. Acad. Sci. U.S.A.

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We show that the general anesthetics xenon, sulfur hexafluoride, nitrous oxide, and chloroform cause rapid increases of different magnitude and time course in the electron spin content of Drosophila. With the exception of CHCl 3 , these changes are reversible. Anesthetic-resistant mutant strains of Drosophila exhibit a different pattern of spin responses to anesthetic. In two such mutants, the spin response to CHCl 3 is absent. We propose that these spin changes are caused by perturbation of the electronic structure of proteins by general anesthetics. Using density functional theory, we show that general anesthetics perturb and extend the highest occupied molecular orbital of a nine-residue α-helix. The calculated perturbations are qualitatively in accord with the Meyer-Overton relationship and some of its exceptions. We conclude that there may be a connection between spin, electron currents in cells, and the functioning of the nervous system.

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“…[35][36][37] However, these publications as well as sound quantitative tests falsifying lipid theory-based predictions remained largely unnoticed. 38,39 The tide began to turn only after two scientists framed the problem in 'familiar' terms.…”

Section: The Crisis Of Lipoid Theories Leaves the Paradigm Unscathedmentioning

confidence: 99%

The Quest for a Unified Model of Anesthetic Action

Perouansky

2012

Anesthesiology

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An accepted truism among clinicians and researchers attributes the persistence of the quest for a unitary mechanism of anesthetic action to the lasting influence of Hans Meyer and Ernest Overton. This article presents a different view: the experiments that led to the Meyer-Overton rule were the consequence-not the source-of a unitary paradigm that was formulated by Claude Bernard a quarter of a century earlier. Bernard firmly believed that the sensitivity to anesthesia was a fundamental criterion that separated 'true life' from 'mere chemistry.' Bernard's scientific authority in the context of 19 th century natural philosophy is responsible for establishing a unified (i.e., unitary mechanism and universality across life forms) paradigm of anesthetic action. Meyer and Overton's work was targeted at systematizing and solidifying existing knowledge within this paradigm, not at discovering novelty, and its publication did not substantially affect contemporary research. Claude Bernard's paradigm, by contrast, still influences investigations of mechanisms of anesthetic action. PARADIGMS play a frequently unrecognized (or at least underappreciated) role in the progress of science. In fact, it has been claimed that "normal science" does not occur outside of paradigms.1 Although paradigms are essential, they do not a priori ensure ultimate success at solving the scientific puzzle to which they are being applied. Paradigms must prove utility at some stage to gain acceptance, but over time and in the absence of evolution, they may also thwart innovative thinking. Has the pursuit of a unified mechanism of anesthesia been driven by a cumulative aggregation of knowledge? Or has it been simply the result of an implicit, subconscious, unyielding paradigm?In 1950, Thomas Butler, M.D. of Baltimore, Maryland † (Associate Professor of Pharmacology, Johns Hopkins School of Medicine, 1910Medicine, -1993 remarked 'there is reason to doubt whether the search for a single theory … may not have been a misguided effort. The metaphysical desire for unification … may well have delayed arrival at a more satisfactory solution.' 2 More than 60 yr later, one may wonder whether our understanding of cognitive neuroscience in general and anesthetic mechanisms in particular would be different now if research into the latter had not been shackled to the pursuit of a unifying theory of anesthetic action. A Superficial and Inaccurate View of HistoryInasmuch as history of research into anesthetic mechanisms is mentioned at all in contemporary reviews and textbooks, it is mostly limited to a cursory mention of the somewhat antiquated and obscure terms 'lipoid' and 'unitary.' Separation is frequently not even attempted, and for many readers these Address correspondence to Dr. Perouansky: Department of Anesthesiology, B6/319 CSC, 600 Highland Avenue, Madison, Wisconsin 53792. mperouansky@wisc.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. ANESTHESIOLOGY'S art...

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Interactions of Inert Anesthetic Gases With Proteins

Cited by 49 publications

References 0 publications

Critical Role of Water in the Binding of Volatile Anesthetics to Proteins

Critical Role of Water in the Binding of Volatile Anesthetics to Proteins

Electron spin changes during general anesthesia in Drosophila

The Quest for a Unified Model of Anesthetic Action

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