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Do general anaesthetics act by competitive binding to specific receptors?
Abstract
Most proteins are insensitive to the presence of anaesthetics at concentrations which induce general anaesthesia, while some are inhibited by certain agents but not others. Here we show that, over a 100,000-fold range of potencies, the activity of a pure soluble protein (firefly luciferase) can be inhibited by 50% at anaesthetic concentrations which are essentially identical to those which anaesthetize animals. This identity holds for inhalational agents (such as halothane, methoxyflurane and chloroform), aliphatic and aromatic alcohols, ketones, ethers and alkanes. This finding is all the more striking in view of the fact that the inhibition is shown to be competitive in nature, with anaesthetic molecules competing with substrate (luciferin) molecules for binding to the protein. We show that the anaesthetic-binding site can accommodate only one large, but more than one small, anaesthetic molecule. The obvious mechanism suggested by our results is that general anaesthetics, despite their chemical and structural diversity, act by competing with endogenous ligands for binding to specific receptors.
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“together with the discovery of stereoselective optical isomers of anesthetics with identical lipid solubility but reduced potency, called into question the non-specific lipid theory of anesthetic action [32].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [32]
In the citing paper
“Subsequent recognition that distinct anesthetic drugs could similarly inhibit the protein firefly luciferase over an identical six-order of magnitude range in a cell-free environment”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [32]
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A Unitary Anesthetic Binding Site at High Resolution
Vedula, L. S., Brannigan, G. H., Economou, N. J., Jin, X., Hall, M. A., Liu, R., Rossi, M. J., Dailey, W. P., Grasty, K. C., Klein, M. L., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.017814 · Cited by 78
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“in explaining anesthesia via proteins acting as specific receptors for anesthetics.(5) However, inconsistencies with this theory called for a further updates.”
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“An important demonstration that proteins had the potential to be relevant anaesthetic targets resulted from studies by Franks and Lieb.7 They demonstrated that the activity of a soluble protein, firefly luciferase, in the absence of lipid, was influenced by a variety of general anaesthetics.7 Subsequently, numerous ca…”
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Mutations Affecting Sensitivity to Ethanol in the Nematode, Caenorhabditis elegans
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“…anesthetics (halothane, methoxyflurane, chloroform), alcohols, ketones, ethers, and alkanes are able to inhibit the activity of pure firefly luciferase at anesthetic concentrations in a competitive manner with the binding site accomodating one large or two small molecules (Franks and Lieb, 1984).”
BackgroundCellular and Molecular Physiology of Alcohol Actions in the Nervous System
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Metadata
- Authors
- Franks, N. P., & Lieb, W. R.
- Affiliations
- Imperial College London (GB)
- King's College London (GB)
- ORCID
- Franks, N. P.
- Venue
- Nature
- Published
- 1984-08
- Volume
- 310
- Issue
- 5978
- Pages
- 599-601
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2028401432
- Cited by
- 572
- References
- 24
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 8 · 2023: 8 · 2022: 9 · 2021: 9 · 2020: 11 · 2019: 12 · 2018: 7 · 2017: 15 · 2016: 12 · 2015: 16 · 2014: 20 · 2013: 21 · 2012: 22
- FWCI
- 24.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- general anesthetics, competitive binding, firefly luciferase, protein inhibition, competitive inhibition, inhalational anesthetics, halothane, methoxyflurane, chloroform
- MeSH terms
- Hexanols, Anesthesia, General, Anesthetics, Animals, Coleoptera, Binding Sites, Binding, Competitive, Fatty Alcohols, Halothane, Kinetics, Luciferases, Molecular Conformation, Protein Binding, Protein Conformation
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