A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans
Open accessAbstract
The molecular mechanisms underlying general anesthesia are unknown. For volatile general anesthetics (VAs), indirect evidence for both lipid and protein targets has been found. However, no in vivo data have implicated clearly any particular lipid or protein in the control of sensitivity to clinical concentrations of VAs. Genetics provides one approach toward identifying these mechanisms, but genes strongly regulating sensitivity to clinical concentrations of VAs have not been identified. By screening existing mutants of the nematode Caenorhabditis elegans , we found that a mutation in the neuronal syntaxin gene dominantly conferred resistance to the VAs isoflurane and halothane. By contrast, other mutations in syntaxin and in the syntaxin-binding proteins synaptobrevin and SNAP-25 produced VA hypersensitivity. The syntaxin allelic variation was striking, particularly for isoflurane, where a 33-fold range of sensitivities was seen. Both the resistant and hypersensitive mutations decrease synaptic transmission; thus, the indirect effect of reducing neurotransmission does not explain the VA resistance. As assessed by pharmacological criteria, halothane and isoflurane themselves reduced cholinergic transmission, and the presynaptic anesthetic effect was blocked by the resistant syntaxin mutation. A single gene mutation conferring high-level resistance to VAs is inconsistent with nonspecific membrane-perturbation theories of anesthesia. The genetic and pharmacological data suggest that the resistant syntaxin mutant directly blocks VA binding to or efficacy against presynaptic targets that mediate anesthetic behavioral effects. Syntaxin and syntaxin-binding proteins are candidate anesthetic targets.
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No single gene mutation completely removes volatile anesthetic responsiveness.
“no single gene mutation fully ablates volatile anesthetic responsiveness.”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [14]
Mutations that enhance presynaptic release cause volatile anesthetic resistance, while those that impair release cause hypersensitivity.
“In general, mutations that enhanced presynaptic release led to volatile anesthetic resistance, whereas those that impaired release produced a hypersensitive phenotype [14].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [14]
C. elegans with altered volatile anesthetic sensitivity have syntaxin mutations that can cause resistance or hypersensitivity depending on the allele.
“Worms with altered sensitivity to volatile anesthetics were found to have mutations in syntaxin that could manifest either with resistance or hypersensitivity, depending on the mutated allele.”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [14]
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Self-citation
- Authors
- van Swinderen, B., Saifee, O., Shebester, L., Roberson, R., Nonet, M. L., & Crowder, C. M.
- Affiliations
- Departments of Anesthesiology, Molecular Biology and Pharmacology, and Anatomy and Neurobiology, Division of Biology and Biomedical Sciences, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110
- Washington University in St. Louis (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-03-02
- Volume
- 96
- Issue
- 5
- Pages
- 2479-2484
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC26810
- OpenAlex
- W2111447389
- Cited by
- 106
- References
- 38
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 4 · 2014: 5 · 2013: 2 · 2012: 4
- FWCI
- 5.43
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01gm059781-08)
- National Institute of General Medical Sciences (R01GM-059781)
- Topics
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Keywords
- volatile anesthetics, general anesthesia, syntaxin, neomorphic mutations, isoflurane, halothane, synaptobrevin, SNAP-25, synaptic transmission, cholinergic neurotransmission, anesthetic resistance, Caenorhabditis elegans
- MeSH terms
- Aldicarb, Amino Acid Sequence, Animals, Base Sequence, Caenorhabditis, Crosses, Genetic, Genes, Dominant, Halothane, Isoflurane, Membrane Proteins, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Synaptic Transmission, Phenotype, Regression Analysis, Disorders of Sex Development, Sequence Alignment, Synaptophysin, Genes, Helminth, Sequence Homology, Amino Acid, Anesthetics, Inhalation, Qa-SNARE Proteins, Synaptosomal-Associated Protein 25
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