Cited by 574Anesthesia and Sedative AgentsAnesthesia and Neurotoxicity ResearchNeuroscience and Neuropharmacology Research

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Do general anaesthetics act by competitive binding to specific receptors?

Franks, N. P., Lieb, W. R.·1984·Nature

DOI 10.1038/310599a0

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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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“A seminal 1984 study by Franks and Lieb demonstrated that anesthetic concentrations of halothane could inhibit the activity of purified soluble proteins (e.g., firefly luciferase) by up to 50% [38].”
Are “GABAergic” Agents Really So Selective for GABA? Implications for Single- versus Multi-Site Hypotheses From Promiscuous Behavior of Anesthetics and Their Molecular Targets In Vitro
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“5,6 However, anaesthetics appear to have effects on many other proteins, receptors, and channels.”
Background
1 + 1 = 4? Balanced anaesthesia: A sum that is greater than its parts
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“…general acceptance of the importance of anaesthetic–protein interactions occurred in 1984 when a study by Franks and Lieb showed that firefly luciferase activity is competitively inhibited by 50% at concentrations of anaesthetic identical to those used to anaesthetize animals (Franks & Lieb, 1984).”
Background
Components of General Anesthesia: History of the Concept Transformation
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“Using electrophysiological techniques, Franks and Lieb (1984) showed that anesthetics act on central NMDA-Rs, a third type of ligand-gated cation channels (Fig.”
BackgroundMethod
Effects of Alcohols on A-Type K+ Currents in Lymnaea Neurons
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The Location and Nature of General Anesthetic Binding Sites on the Active Conformation of Firefly Luciferase; A Time Resolved Photolabeling Study
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“Such a mechanism might allow the pocket and vestibule to accommodate ligands of variable structure, which would be consistent with the wide range of agents that inhibit luciferase [7,9,25,31].”
Background
Volatile anesthetics and a volatile convulsant differentially affect GABAA receptor–chloride channel complex
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BackgroundInfluential
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Lipid solubility is not the sole criterion for the inhibition of a Ca2+-activated K+ channel by alcohols
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Do Direct Protein/Anesthetic Interactions Underlie the Mechanism of General Anesthesia?
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Self-citation
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Assessing anesthetic activity through modulation of the membrane dipole potential
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Effect of the General Anaesthetic Ketamine on Electrical and Ca2+ Signal Propagation in Arabidopsis thaliana
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Background
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Saturable Binding of Anesthetics to Nicotinic Acetylcholine Receptors
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Molecular Mechanisms of Ethanol and Anesthetic Actions: Lipid- and Protein-Based Theories
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Authors: Franks, N. P., & Lieb, W. R.
Affiliations: Imperial College London (GB)
King's College London (GB)
ORCID: Franks, N. P.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1984-08
Volume: 310
Issue: 5978
Pages: 599-601
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/310599a0
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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Do general anaesthetics act by competitive binding to specific receptors?

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