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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
Author(s) -
Ko Hyuk Wan,
Han Kong Sook,
Kim Eun Young,
Ryu Bo Rum,
Yoon Won Joo,
Jung YongKeun,
Kim Seong Up,
Gwag Byoung Joo
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0742455.x
Subject(s) - proteases , caspase , apoptosis , neuroprotection , neurotoxicity , programmed cell death , biology , p38 mitogen activated protein kinases , excitotoxicity , microbiology and biotechnology , calpain , protein kinase a , kinase , biochemistry , chemistry , pharmacology , toxicity , enzyme , organic chemistry
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 hypoxicischemic and neurodegenerative diseases. Mouse cortical cell cultures underwent widespread neuronal apoptosis 24 h following exposure to 10‐30 n M calyculin A, a selective inhibitor of Ser/Thr phosphatase I and IIA. Activity of p38 was increased 2‐4 h following exposure to 30 n M calyculin A. Addition of 3‐10 μ M 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 n M 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 μ M N ‐benzyloxycarbonyl‐Val‐Ala‐Asp‐fluoromethyl ketone (z‐VAD‐fmk), a broad‐spectrum inhibitor of caspases, but incompletely by 10 μ M PD169316. Calyculin A neurotoxicity was partially sensitive to 100 μ M z‐VAD‐fmk. Cotreatment with 10 μ M PD169316 and 100 μ M 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 μ M NMDA. Thus, caspase‐3‐like proteases and p38 likely contribute to calyculin A‐induced neuronal apoptosis but not NMDA‐induced neuronal necrosis.