title: Synaptic PDZ domain-mediated protein interactions are disrupted by inhalational anesthetics.
abstract: 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.
authors.affiliation: Department of Anesthesiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Fang
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Tao
authors.forename: Fahu
authors.initials: F
authors.lastname: He
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
authors.forename: Claire F
authors.initials: CF
authors.lastname: Levine
authors.forename: Peizhong
authors.initials: P
authors.lastname: Mao
authors.forename: Feng
authors.initials: F
authors.lastname: Tao
authors.forename: Chih-Ling
authors.initials: CL
authors.lastname: Chou
authors.forename: Scheherazade
authors.initials: S
authors.lastname: Sadegh-Nasseri
authors.forename: Roger A
authors.initials: RA
authors.lastname: Johns
mesh_terms: 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
chemical_list: 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