Effect of disrupting N-methyl-d-aspartate receptor-postsynaptic density protein-95 interactions on the threshold for halothane anesthesia in mice
Open accessAbstract
Background: The authors' previous studies have shown that clinically relevant concentrations of inhalational anesthetics dose-dependently and specifically inhibit the PSD-95, Dlg, and ZO-1 (PDZ) domain-mediated protein interactions between postsynaptic density protein 95 (PSD-95) and N-methyl-d-aspartate receptors, and that the knockdown of spinal PSD-95 by intrathecal injection of PSD-95 antisense oligodeoxynucleotide significantly reduces the minimum alveolar anesthetic concentration for isoflurane in rats. Methods: The authors constructed a fusion peptide, Tat-PSD-95 PDZ2, comprising the second PDZ domain of PSD-95, which can specifically disrupt PSD-95 PDZ2-mediated protein interactions by binding to its interaction partner. By intraperitoneal injection of this fusion peptide into mice, the authors investigated the effect of disrupting the PSD-95 PDZ2-mediated protein interactions on the threshold for halothane anesthesia. Results: Systemically injected fusion peptide Tat-PSD-95 PDZ2 was delivered into the central nervous system, disrupted the protein-protein interactions between N-methyl-d-aspartate receptor NR2 subunits and PSD-95, and significantly reduced the minimum alveolar anesthetic concentration and righting reflex EC50 for halothane. Conclusions: By disrupting PSD-95 PDZ2 domain-mediated protein interactions, intraperitoneal injection of cell-permeant fusion peptide Tat-PSD-95 PDZ2 dose-dependently reduces the threshold for halothane anesthesia. These results suggest that PDZ domain-mediated protein interactions at synapses in the central nervous system might play an important role in the molecular mechanisms of halothane anesthesia.
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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 [89]
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 [89]
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The Biology of General Anesthesia from Paramecium to Primate
Kelz, M. B., & Mashour, G. A. (2019) · Current Biology · doi:10.1016/j.cub.2019.09.071 · Cited by 151 · see citing works
- Authors
- Tao, F., & Johns, R. A.
- Affiliations
- Johns Hopkins University (US)
- Professor.
- Venue
- Anesthesiology
- Published
- 2008-05-01
- Volume
- 108
- Issue
- 5
- Pages
- 882-887
- ISSN
- 0003-3022 (ISSN-L)
- PMC
- PMC2424269
- OpenAlex
- W2040864710
- Cited by
- 13
- References
- 25
- Citations by year
- 2025: 1 · 2022: 2 · 2020: 1 · 2019: 1 · 2018: 1 · 2016: 1 · 2015: 2 · 2013: 1
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Anesthesiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM049111, GM049111)
- National Institute of Neurological Disorders and Stroke (NS44219, R01NS044219)
- 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
- halothane anesthesia, NMDA receptor, PSD-95, PDZ domain, protein-protein interaction, fusion peptide, minimum alveolar concentration, righting reflex, intraperitoneal injection, synaptic proteins, inhalational anesthetics
- MeSH terms
- Disks Large Homolog 4 Protein, Animals, Halothane, Male, Membrane Proteins, Mice, Inbred C57BL, Recombinant Fusion Proteins, Reflex, Gene Products, tat, Receptors, N-Methyl-D-Aspartate, Anesthetics, Inhalation, Intracellular Signaling Peptides and Proteins, Mice, Guanylate Kinases
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