Targeted disruption of PSD-93 gene reduces platelet-activating factor-induced neurotoxicity in cultured cortical neurons

Exp Neurol. 2004 Sep;189(1):16-24. doi: 10.1016/j.expneurol.2004.05.013.

Abstract

PSD-93, a molecular adaptive protein, binds to and clusters the N-methyl-D-aspartate (NMDA) receptor and assembles a specific set of signaling proteins (for example neuronal nitric oxide synthase, nNOS) around the NMDA receptor at synapses in the central nervous system. This suggests that PSD-93 might mediate many NMDA receptor-dependent physiological and pathophysiological functions. We report here that PSD-93 colocalizes and interacts with the NMDA receptor and neuronal nitric oxide synthase in cultured cortical neurons. Targeted disruption of PSD-93 gene significantly prevented NMDA receptor-nitric oxide signaling-dependent neurotoxicity triggered via platelet-activating factor (PAF) receptor activation. In addition, the deficiency of PSD-93 markedly attenuated platelet-activating factor-induced increase in cyclic guanosine 3',5'-monophosphate (cGMP) and prevented platelet-activating factor-promoted formation of NMDA receptor-neuronal nitric oxide synthase complex. These findings indicate that PSD-93 is involved in the NMDA receptor--nitric oxide-mediated pathological processing of neuronal damage triggered via platelet--activating factor receptor activation. Since platelet-activating factor is a potent neuronal injury mediator during the development of brain trauma, seizures, and ischemia, the present work suggests that PSD-93 might contribute to molecular mechanisms of neuronal damage in these brain disorders.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western / methods
  • Cell Count / methods
  • Cell Death / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Cyclic GMP / metabolism
  • Diterpenes / pharmacology
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Embryo, Mammalian
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Fluorescent Antibody Technique / methods
  • Ginkgolides
  • Guanylate Kinases
  • Intracellular Signaling Peptides and Proteins
  • Lactones / pharmacology
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Microscopy, Confocal / methods
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nerve Tissue Proteins / deficiency*
  • Nerve Tissue Proteins / genetics
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / physiology
  • Neurotoxins / antagonists & inhibitors
  • Neurotoxins / toxicity*
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type I
  • Platelet Activating Factor / antagonists & inhibitors
  • Platelet Activating Factor / toxicity*
  • Precipitin Tests / methods
  • Propidium
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • Diterpenes
  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Ginkgolides
  • Intracellular Signaling Peptides and Proteins
  • Lactones
  • Membrane Proteins
  • NR2A NMDA receptor
  • Nerve Tissue Proteins
  • Neurotoxins
  • Platelet Activating Factor
  • Receptors, N-Methyl-D-Aspartate
  • postsynaptic density proteins
  • Propidium
  • Dizocilpine Maleate
  • ginkgolide B
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nos1 protein, mouse
  • Dlg2 protein, mouse
  • Guanylate Kinases
  • Cyclic GMP
  • NG-Nitroarginine Methyl Ester