Abstract
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Anesthesiology and Pain Medicine
Cited by
12 articles.
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