Effect of disrupting N-methyl-d-aspartate receptor-postsynaptic density protein-95 interactions on the threshold for halothane anesthesia in mice.
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.
Tao
Feng
F
Department of Anesthesiology and Critical Care Medicine,Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Johns
Roger A
RA
D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D015696:Gene Products, tat / Q000235:genetics / Q000502:physiology; D051528:Guanylate Kinases; D006221:Halothane / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D012018:Reflex / Q000187:drug effects / Q000502:physiology
D018685:Anesthetics, Inhalation; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D015696:Gene Products, tat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D051528:Guanylate Kinases; D006221:Halothane