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Nitric oxide prevents 6‐hydroxydopamine‐induced apoptosis in PC12 cells through cGMP‐dependent PI3 kinase/Akt activation
Author(s) -
HA KWON-SOO,
KIM KI-MO,
KWON YOUNG-GUEN,
BAI SE-KYUNG,
NAM WOO-DONG,
YOO YOUNG-MIN,
KIM PETER K. M.,
CHUNG HUN-TAEG,
BILLIAR TIMOTHY R.,
KIM YOUNG-MYEONG
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0738com
Subject(s) - protein kinase b , wortmannin , cgmp dependent protein kinase , microbiology and biotechnology , apoptosis , chemistry , pi3k/akt/mtor pathway , hydroxydopamine , signal transduction , kinase , nitric oxide , ly294002 , phosphorylation , cytochrome c , protein kinase a , biology , mitogen activated protein kinase kinase , biochemistry , endocrinology , dopaminergic , organic chemistry , dopamine
Nitric oxide (NO) functions not only as an important signaling molecule in the brain by producing cGMP, but also regulates neuronal cell apoptosis. The mechanism by which NO regulates apoptosis is unclear. In this study, we demonstrated that NO, produced either from the NO donor S ‐nitroso‐N‐acetyl‐ D,L ‐penicillamine (SNAP) or by transfection of neuronal NO synthase, suppressed 6‐hydroxydopamine (6‐OHDA)‐induced apoptosis in PC12 cells by inhibiting mitochondrial cytochrome c release, caspase‐3 and ‐9 activation, and DNA fragmentation. This protection was significantly reversed by the soluble guanylyl cyclase inhibitor 1H‐(1,2,4)‐oxadiazole[4,3‐a]quinoxalon‐1‐one, indicating that cGMP is a key mediator in NO‐mediated anti‐apoptosis. Moreover, the membrane‐permeable cGMP analog 8‐Br‐cGMP inhibited 6‐OHDA‐induced apoptosis. These anti‐apoptotic effects of SNAP and 8‐Br‐cGMP were suppressed by cGMP‐dependent protein kinase G (PKG) inhibitor KT5823, indicating that PKG is a downstream signal mediator in the suppression of apoptosis by NO and cGMP. Both SNAP and 8‐Br‐cGMP induced endogenous Akt activation and Bad phosphorylation, resulting in the inhibition of Bad translocation to mitochondria;these effects were inhibited by KT5823 and the phosphatidylinositol 3‐kinase (PI3K) inhibitors LY294002 and Wortmannin. Our data suggest that the NO/cGMP pathway suppresses 6‐OHDA‐induced PC12 cell apoptosis by suppressing the mitochon‐drial apoptosis signal via PKG/PI3K/Akt‐dependent Bad phosphorylation.—Ha, K.‐S., Kim, K. M., Kwon, Y.‐G., Bai, S.‐K., Nam, W.‐D., Yoo, Y.‐M., Kim, P. K. M., Chung, H.‐T., Billiar, T. R., Kim, Y.‐M. Nitric oxide prevents 6‐hydroxydopamine‐induced apoptosis in PC12 cells through cGMP‐dependent PI3 kinase/Akt activation. FASEB J. 17, 1036–1047 (2003)