Synergetic activation of p38 mitogen-activated protein kinase and caspase-3-like proteases for execution of calyculin A-induced apoptosis but not N-methyl-D-aspartate-induced necrosis in mouse cortical neurons

Hyuk Wan Ko, Kong Sook Han, Eun Young Kim, Bo Rum Ryu, Won Joo Yoon, Yong Keun Jung, Seong Up Kim, Byoung Joo Gwag

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Abstract

We examined the possibility that p38 mitogen-activated protein kinase and caspase-3 would be activated for execution of apoptosis and excitotoxicity, the two major types of neuronal death underlying hypoxic- ischemic and neurodegenerative diseases. Mouse cortical cell cultures underwent widespread neuronal apoptosis 24 h following exposure to 10-30 nM calyculin A, a selective inhibitor of Ser/Thr phosphatase I and IIA. Activity of p38 was increased 2-4 h following exposure to 30 nM calyculin A. Addition of 3-10 μM PD169316, a selective p38 inhibitor, partially attenuated calyculin A neurotoxicity. Activity of caspase-3-like proteases was increased in cortical cell cultures exposed to 30 nM calyculin A for 8-16 h as shown by cleavage of DEVD-p-nitroanilide and phosphorylated tau. Proteolysis of tau was completely blocked by addition of 100 μM N-benzyloxycarbonyl-Val-Ala- Asp-fluoromethyl ketone (z-VAD-fmk), a broad-spectrum inhibitor of caspases, but incompletely by 10 μM PD169316. Calyculin A neurotoxicity was partially sensitive to 100 μM z-VAD-fmk. Cotreatment with 10 μM PD169316 and 100 μM z-VAD-fmk showed additive neuroprotection against calyculin A. Neither PD169316 nor z-VAD-fmk showed a beneficial effect against excitotoxic neuronal necrosis induced by exposure to 20 μM NMDA. Thus, caspase-3-like proteases and p38 likely contribute to calyculin A-induced neuronal apoptosis but not NMDA-induced neuronal necrosis.

Original languageEnglish
Pages (from-to)2455-2461
Number of pages7
JournalJournal of Neurochemistry
Volume74
Issue number6
DOIs
Publication statusPublished - 2000 Jun 5

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

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