title: NMDA receptor-mediated Ca(2+) influx triggers nucleocytoplasmic translocation of diacylglycerol kinase ζ under oxygen-glucose deprivation conditions, an in vitro model of ischemia, in rat hippocampal slices.
abstract: Diacylglycerol kinase (DGK) plays a key role in pathophysiological cellular responses by regulating the levels of a lipid messenger diacylglycerol. Of DGK isozymes, DGKζ localizes to the nucleus in various cells such as neurons. We previously reported that DGKζ translocates from the nucleus to the cytoplasm in hippocampal CA1 pyramidal neurons after 20 min of transient forebrain ischemia. In this study, we examined the underlying mechanism of DGKζ translocation using hippocampal slices exposed to oxygen-glucose deprivation (OGD) to simulate an ischemic model of the brain. DGKζ-immunoreactivity gradually changed from the nucleus to the cytoplasm in CA1 pyramidal neurons after 20 min of OGD and was never detected in the nucleus after reoxygenation. Intriguingly, DGKζ was detected in the nucleus at 10 min OGD whereas the following 60 min reoxygenation induced complete cytoplasmic translocation of DGKζ. Morphometric analysis revealed that DGKζ cytoplasmic translocation correlated with nuclear shrinkage indicative of an early process of neuronal degeneration. The translocation under OGD conditions was blocked by NMDA receptor (NMDAR) inhibitor, and was induced by activation of NMDAR. Chelation of the extracellular Ca(2+) blocked the translocation under OGD conditions. These results show that DGKζ cytoplasmic translocation is triggered by activation of NMDAR with subsequent extracellular Ca(2+) influx. Furthermore, inhibition of PKC activity under OGD conditions led to nuclear retention of DGKζ in about one-third of the neurons, suggesting that PKC activity partially regulates DGKζ cytoplasmic translocation. These findings provide clues to guide further investigation of glutamate excitotoxicity mechanisms in hippocampal neurons.
authors.affiliation: Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Yasukazu
authors.initials: Y
authors.lastname: Hozumi
authors.forename: Masashi
authors.initials: M
authors.lastname: Okada
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Ohta
authors.forename: Masaru
authors.initials: M
authors.lastname: Aoyagi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fujii
authors.forename: Kaoru
authors.initials: K
authors.lastname: Goto
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D004195:Disease Models, Animal; D005947:Glucose / Q000172:deficiency* / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D019852:Diacylglycerol Kinase; C508008:diacylglycerol kinase zeta, rat; D005947:Glucose; D010100:Oxygen; D002118:Calcium