Synaptic PDZ domain-mediated protein interactions are disrupted by inhalational anesthetics.
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.
Fang
Ming
M
Department of Anesthesiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Tao
Yuan-Xiang
YX
He
Fahu
F
Zhang
Mingjie
M
Levine
Claire F
CF
Mao
Peizhong
P
Tao
Feng
F
Chou
Chih-Ling
CL
Sadegh-Nasseri
Scheherazade
S
Johns
Roger A
RA
D018685:Anesthetics, Inhalation / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000378:metabolism; D006221:Halothane / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry; D019001:Nitric Oxide Synthase / Q000737:chemistry; D052248:Nitric Oxide Synthase Type I; D010455:Peptides / Q000737:chemistry; D011233:Precipitin Tests; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D013997:Time Factors; D020798:Two-Hybrid System Techniques
D018685:Anesthetics, Inhalation; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C501451:Mpp2 protein, rat; D009419:Nerve Tissue Proteins; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D005982:Glutathione Transferase; D006221:Halothane