Synaptic PDZ domain-mediated protein interactions are disrupted by inhalational anesthetics
Open accessAbstract
Anesthetics exert multiple effects on the central nervous system through altering synaptic transmission, but the mechanisms for this process are poorly understood. PDZ domain-mediated protein interactions play a central role in organizing signaling complexes around synaptic receptors for efficient signal transduction. We report here that clinically relevant concentrations of inhalational anesthetics dose-dependently and specifically inhibit the PDZ domain-mediated protein interaction between PSD-95 or PSD-93 and the N-methyl-d-aspartate receptor or neuronal nitric-oxide synthase. These inhibitory effects are immediate, potent, and reversible and occur at a hydrophobic peptide-binding groove on the surface of the second PDZ domain of PSD-95 in a manner relevant to anesthetic action. These findings reveal the PDZ domain as a new molecular target for inhalational anesthetics.
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Volatile anesthetics reversibly disrupt interactions of NMDA and AMPA receptors with scaffolding proteins, independently altering volatile anesthetic requirements.
“volatile anesthetics reversibly disrupt the interactions of NMDA and AMPA receptors with scaffolding proteins. This independently alters volatile anesthetic requirements.”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [90]
Anesthetics disrupt glutamate receptor signaling through multiple pathways to modulate synaptic function.
“Thus, anesthetics disrupt glutamate receptor signaling through multiple pathways to modulate synaptic function [89, 90].”
From The Biology of General Anesthesia from Paramecium to Primate (2019) · cites this paper as [90]
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References 59 · Cited by 34
- Authors
- Fang, M., Tao, Y.-X., He, F., Zhang, M., Levine, C. F., Mao, P., Tao, F., Chou, C.-L., Sadegh-Nasseri, S., & Johns, R. A.
- Affiliations
- Johns Hopkins University (US)
- Hong Kong University of Science and Technology (HK)
- Corresponding author
- Johns, Roger A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-09
- Volume
- 278
- Issue
- 38
- Pages
- 36669-36675
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2111620202
- Cited by
- 34
- References
- 59
- Citations by year
- 2025: 1 · 2022: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 6 · 2015: 1 · 2014: 1 · 2013: 1 · 2012: 1
- FWCI
- 0.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (GM 49111, R01GM049111)
- National Institute of Neurological Disorders and Stroke (NS44219, R01NS044219)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
- Keywords
- inhalational anesthetics, PDZ domain, PSD-95, PSD-93, NMDA receptor, neuronal nitric oxide synthase, synaptic transmission
- MeSH terms
- Disks Large Homolog 4 Protein, Animals, Dose-Response Relationship, Drug, Glutathione Transferase, Halothane, Membrane Proteins, Models, Molecular, Nerve Tissue Proteins, Magnetic Resonance Spectroscopy, Peptides, Precipitin Tests, Protein Binding, Protein Conformation, Time Factors, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Protein Structure, Tertiary, Anesthetics, Inhalation, Nitric Oxide Synthase, Surface Plasmon Resonance, Two-Hybrid System Techniques, Intracellular Signaling Peptides and Proteins, Rats, Nitric Oxide Synthase Type I
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