Multiple Specific Binding Targets for Inhaled Anesthetics in the Mammalian Brain

Eckenhoff, Maryellen F.; Chan, Kin; Eckenhoff, Roderic G.

doi:10.1124/jpet.300.1.172

Cited by 41 publications

(23 citation statements)

References 21 publications

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“…The high effective concentration of general anesthetics is consistent with their relatively featureless molecular structures and weak binding energetics [7]. In fact, widespread binding sites of volatile anesthetics are shown in rat brain slices [71] that may include membrane proteins as well as soluble proteins [72]. These fi ndings, together, strongly support the notion that volatile anesthetics interact with multiple protein sites to exert clinical effects.…”

Section: Unique Pharmacology Of General Anestheticssupporting

confidence: 52%

Mechanisms of anesthetic actions and the brain

Ishizawa

2007

J Anesth

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The neural mechanisms behind anesthetic-induced behavioral changes such as loss of consciousness, amnesia, and analgesia, are insufficiently understood, though general anesthesia has been of tremendous importance for the development of medicine. In this review, I summarize what is currently known about general anesthetic actions at different organizational levels and discuss current and future research, using systems neuroscience approaches such as functional neuroimaging and quantitative electrophysiology to understand anesthesia actions at the integrated brain level.

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Section: Unique Pharmacology Of General Anestheticssupporting

confidence: 52%

Mechanisms of anesthetic actions and the brain

Ishizawa

2007

J Anesth

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“…We previously estimated that 15% of PDB entries have cavities large enough to bind halothane (10). The larger percentage in this study is possibly because of the fact that membrane and oligomeric proteins have larger and more numerous cavities than the small soluble ones that comprise most of the PDB entries to date (21).…”

Section: Fig 2 Halothane Labeling Quantitation a Incorporation Ofmentioning

confidence: 62%

“…The use of photoaffinity labeling with halothane has overcome some of these difficulties (5) and has allowed demonstration of specific and selective binding sites in a wide variety of both membrane (6) and soluble (7,8) protein models. Extending the results of these studies to the mammalian central nervous system, we have also demonstrated widespread binding (9) and multiple specific targets (10) for the anesthetic halothane. Interestingly, although similar haloalkanes (e.g.…”

mentioning

confidence: 56%

Inhalational Anesthetic-binding Proteins in Rat Neuronal Membranes

Jin

Liu

Asbury³

et al. 2004

Journal of Biological Chemistry

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Molecular targets of inhaled anesthetics must be represented in the group that specifically bind these drugs, but the paucity of direct binding data has limited the number of candidates for further evaluation. To find candidate targets, we used a combination of photolabeling, two-dimensional gel electrophoresis, and mass spectrometry to identify halothane-binding targets in rat neuronal membranes. Of the 265 spots detected on the two-dimensional gels, 90 were labeled by [14 C]halothane, and 34 were identified. Mitochondrial proteins, especially respiratory complex and voltage-dependent anion channels, dominated the labeled group, and there were several examples of subunit-and state-dependent binding. A significant correlation was found between internal protein cavities and binding in a group of proteins with high resolution structures. Therefore, in addition to identifying novel neuronal targets, these data suggest a general molecular feature, the buried cavity, as a dominant attribute of volatile anesthetic-binding sites found in a limited number of neuronal membrane proteins.

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“…This indicates that our previous estimate of about 15%, based on cavity volume alone [8], is high. The basis for this greater-than-expected degree of selectivity relate to host-guest chemistry, cavity sterics, and lining reside character.…”

Section: Discussionmentioning

confidence: 88%