The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.
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]
Citations
Cites
Fundamentals of Enzyme Kinetics
Cornish-Bowden, A. J. (1979) · Elsevier eBooks · doi:10.1016/c2013-0-04130-8 · Cited by 2,079
Molecular mechanisms of general anaesthesia
Franks, N. P., & Lieb, W. R. (1982) · Nature · doi:10.1038/300487a0 · Cited by 431
Self-citationFundamentals of Enzyme Kinetics
Gutfreund, H. (1980) · FEBS Letters · doi:10.1016/0014-5793(80)80546-1 · Cited by 387
Kinetics of the firefly luciferase catalyzed reactions
DeLuca, M. A., & McElroy, W. D. (1974) · Biochemistry · doi:10.1021/bi00702a015 · Cited by 258
Where do general anaesthetics act?
Franks, N. P., & Lieb, W. R. (1978) · Nature · doi:10.1038/274339a0 · Cited by 256
Self-citationSOLUBILITY COEFFICIENTS FOR INHALED ANAESTHETICS FOR WATER, OIL AND BIOLOGICAL MEDIA
Steward, A. N., ALLOTT, P. R., Cowles, A. L., & MAPLESON, W. W. (1973) · British Journal of Anaesthesia · doi:10.1093/bja/45.3.282 · Cited by 242
Abraham, M. H. (1982) · Journal of the American Chemical Society · doi:10.1021/ja00372a001 · Cited by 209
Degenerate perturbations of protein structure as the mechanism of anaesthetic action
Richards, C. D., Martin, K. J., Gregory, S., Keightley, C. A., Hesketh, T. R., Smith, G. A., Warren, G., & Metcalfe, J. C. (1978) · Nature · doi:10.1038/276775a0 · Cited by 191
Hydrophobic nature of the active site of firefly luciferase
DeLuca, M. (1969) · Biochemistry · doi:10.1021/bi00829a023 · Cited by 134
Thermodynamic analysis of the relative effectiveness of narcotics
Brink, F., & Posternak, J. M. (1948) · Journal of Cellular and Comparative Physiology · doi:10.1002/jcp.1030320208 · Cited by 132
Flagged first, then by citations
Research works printed but not linked: 4
- Middleton, A. J. & Smith, E. B. Proc. R. Soc. B193, 159–171 (1976).
- Middleton, A. J. & Smith, E. B. Proc. R. Soc. B193, 173–190 (1976).
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- Miller, K. W., Paton, W. D. M., Smith, R. A. & Smith, E. B. Molec. Pharmac. 9, 131–143 (1973).
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Abraham, M. H. (1993) · Chemical Society Reviews · doi:10.1039/cs9932200073 · Cited by 1,968
Molecular and cellular mechanisms of general anaesthesia
Franks, N. P., & Lieb, W. R. (1994) · Nature · doi:10.1038/367607a0 · Cited by 1,786
Self-citationGeneral anaesthesia: from molecular targets to neuronal pathways of sleep and arousal
Franks, N. P. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2372 · Cited by 1,295
Self-citationClinical Electroencephalography for Anesthesiologists
Purdon, P. L., Sampson, A. L., Pavone, K. J., & Brown, E. N. (2015) · Anesthesiology · doi:10.1097/aln.0000000000000841 · Cited by 889
Mechanisms of Actions of Inhaled Anesthetics
Campagna, J. A., Miller, K. W., & Forman, S. A. (2003) · New England Journal of Medicine · doi:10.1056/nejmra021261 · Cited by 805
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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