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ASK1–p38 MAPK/JNK signaling cascade mediates anandamide‐induced PC12 cell death
Author(s) -
Sarker Krishna Pada,
Biswas Kamal Krishna,
Yamakuchi Munekazu,
Lee KiYoung,
Hahiguchi Teruto,
Kracht Michael,
Kitajima Isao,
Maruyama Ikuro
Publication year - 2003
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.1471-4159.2003.01663.x
Subject(s) - p38 mitogen activated protein kinases , microbiology and biotechnology , mapk/erk pathway , ask1 , kinase , programmed cell death , anandamide , apoptosis , protein kinase a , mitogen activated protein kinase , chemistry , mitogen activated protein kinase kinase , biology , biochemistry , cannabinoid receptor , receptor , agonist
Anandamide is a neuroimmunoregulatory molecule that triggers apoptosis in a number of cell types including PC12 cells. Here, we investigated the molecular mechanisms underlying anandamide‐induced cell death in PC12 cells. Anandamide treatment resulted in the activation of p38 mitogen‐activated protein kinase (MAPK), c‐Jun N‐terminal kinase (JNK), and p44/42 MAPK in apoptosing cells. A selective p38 MAPK inhibitor, SB203580, or dn‐JNK, JNK1(A‐F) or SAPKβ(K‐R), blocked anandamide‐induced cell death, whereas a specific inhibitor of MEK‐1/2, U0126, had no effect, indicating that activation of p38 MAPK and JNK is critical in anandamide‐induced cell death. An important role for apoptosis signal‐regulating kinase 1 (ASK1) in this event was also demonstrated by the inhibition of p38 MAPK/JNK activation and death in cells overexpressing dn‐ASK1, ASK1 (K709M). Conversely, the constitutively active ASK1, ASK1ΔN, caused prolonged p38 MAPK/JNK activation and increased cell death. These indicate that ASK1 mediates anandamide‐induced cell death via p38 MAPK and JNK activation. Here, we also found that activation of p38 MAPK/JNK is accompanied by cytochrome c release from the mitochondria and caspase activation (which can be inhibited by SB203580), suggesting that anandamide triggers a mitochondrial dependent apoptotic pathway. The caspase inhibitor, zVAD, and the mitochondrial pore opening inhibitor, cyclosporine A, blocked anandamide‐induced cell death but not p38 MAPK/JNK activation, suggesting that activation of these kinases may occur upstream of mitochondrial associated events.