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Published online 24 July 2000. doi:10.1083/jcb.150.2.335
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© The Rockefeller University Press, 0021-9525/2000//335 $5.00
The Journal of Cell Biology, Volume 150, Number 2, , 2000 335-348

Original Article

p38 Map Kinase Mediates Bax Translocation in Nitric Oxide–Induced Apoptosis in Neurons



Saadi Ghatana, Stephen Larnera, Yoshito Kinoshitaa, Michal Hetmanb, Leena Patela, Zhengui Xiab, Richard J. Youlec, and Richard S. Morrisona

a Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington,
b Department of Environmental Health, University of Washington School of Public Health, Seattle, Washington 98195
c Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892
Department of Neurological Surgery, University of Washington School of Medicine, Box 356470, Seattle, WA 98195-6470.(206) 543-8315(206) 543-9654

yael{at}u.washington.edu

Nitric oxide is a chemical messenger implicated in neuronal damage associated with ischemia, neurodegenerative disease, and excitotoxicity. Excitotoxic injury leads to increased NO formation, as well as stimulation of the p38 mitogen-activated protein (MAP) kinase in neurons. In the present study, we determined if NO-induced cell death in neurons was dependent on p38 MAP kinase activity. Sodium nitroprusside (SNP), an NO donor, elevated caspase activity and induced death in human SH-SY5Y neuroblastoma cells and primary cultures of cortical neurons. Concomitant treatment with SB203580, a p38 MAP kinase inhibitor, diminished caspase induction and protected SH-SY5Y cells and primary cultures of cortical neurons from NO-induced cell death, whereas the caspase inhibitor zVAD-fmk did not provide significant protection. A role for p38 MAP kinase was further substantiated by the observation that SB203580 blocked translocation of the cell death activator, Bax, from the cytosol to the mitochondria after treatment with SNP. Moreover, expressing a constitutively active form of MKK3, a direct activator of p38 MAP kinase promoted Bax translocation and cell death in the absence of SNP. Bax-deficient cortical neurons were resistant to SNP, further demonstrating the necessity of Bax in this mode of cell death. These results demonstrate that p38 MAP kinase activity plays a critical role in NO-mediated cell death in neurons by stimulating Bax translocation to the mitochondria, thereby activating the cell death pathway.

Key Words: caspase • excitotoxicity • neuronal cell death • p53 • mitochondria

© 2000 The Rockefeller University Press

Abbreviations used in this paper: ERK, extracellular signal–regulated kinase; GFP, green fluorescent protein; JNK, c-Jun NH2-terminal kinase; MAP kinase, mitogen-activated protein kinase; MEK, MAP kinase kinase; SNP, sodium nitroprusside; nNOS, neuronal nitric oxide synthase.


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