Targeted disruption of PSD-93 gene reduces platelet-activating factor-induced neurotoxicity in cultured cortical neurons.
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.
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yun
Y
Xu
Bosheng
B
Zhang
Zichun
Z
Hua
Roger A
RA
Johns
David S
DS
Bredt
Yuan-Xiang
YX
Tao
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D006152:Cyclic GMP / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D046934:Ginkgolides; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D007783:Lactones / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal / Q000379:methods; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011233:Precipitin Tests / Q000379:methods; D011419:Propidium; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D004224:Diterpenes; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D046934:Ginkgolides; D047908:Intracellular Signaling Peptides and Proteins; D007783:Lactones; D008565:Membrane Proteins; C120997:NR2A NMDA receptor; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D010972:Platelet Activating Factor; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D011419:Propidium; D016291:Dizocilpine Maleate; C045856:ginkgolide B; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C501445:Dlg2 protein, mouse; D051528:Guanylate Kinases; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester