4.4 Article

Calpain-mediated cleavage of Fbxw7 during excitotoxicity

期刊

NEUROSCIENCE LETTERS
卷 736, 期 -, 页码 -

出版社

ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2020.135265

关键词

Flucw7; Cleavage; Calpain; Glutamate; Excitotoxicity; Middle cerebral artery occlusion (MCAO)

资金

  1. Small Grant for Exploratory Research program through the National Research Foundation of Korea (NRF) - Ministry of Education [2018R1D1A1A02085731]
  2. Brain Research Program through the NRF - Ministry of Science and ICT. [2017M37A1025369]
  3. Mid-Career Research Program through the NRF - Ministry of Science and ICT [2019R1A2C1088793]
  4. National Research Foundation of Korea [2019R1A2C1088793, 2018R1D1A1A02085731] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

向作者/读者索取更多资源

Neuronal cell death induced by ischemic injury has been attributed to glutamate receptor-mediated excitotoxicity, which is known to be accompanied by Ca2+ overload in the cytoplasm with concomitant activation of calcium-dependent mechanisms. More specifically, the overactivation of calpains, calcium-dependent cysteine proteases, have been associated with neuronal cell death following glutamate treatment. Previously, we observed decreased expression levels of F-box/WD repeat domain-containing protein 7 (Fbxw7) after the hyperactivation of cyclin-dependent kinase 5 (Cdk5) in cortical neurons challenged with glutamate. As determined using in vitro calpain cleavage assays, we demonstrated that the cleavage of Fbxw7 was mediated by activated calpain and attenuated in the presence of the calpain inhibitor, calpeptin. Using the rat middle cerebral artery occlusion model, we confirmed that Fbxw7 was indeed cleaved by activated calpain in the ipsilateral cortex. Based on our data, we hypothesize that the negative regulation of Fbxw7 by calpain may contribute to neuronal cell death and that the preservation of Fbxw7 by the inhibition of calpain, Cdk5, or both composes a novel protective mechanism following excitotoxicity.

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