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Opposite regulation of the mitochondrial apoptotic pathway by C2‐ceramide and PACAP through a MAP‐kinase‐dependent mechanism in cerebellar granule cells
Author(s) -
FalluelMorel Anthony,
Aubert Nicolas,
Vaudry David,
Basille Magali,
Fontaine Marc,
Fournier Alain,
Vaudry Hubert,
Gonzalez Bruno J.
Publication year - 2004
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 - 10.1111/j.1471-4159.2004.02810.x
Subject(s) - ceramide , lipid signaling , microbiology and biotechnology , apoptosis , mapk/erk pathway , biology , second messenger system , mitochondrion , adenylate kinase , caspase , signal transduction , programmed cell death , chemistry , biochemistry , receptor
The sphingomyelin‐derived messenger ceramides provoke neuronal apoptosis through caspase‐3 activation, while the neuropeptide pituitary adenylate cyclase‐activating polypeptide (PACAP) promotes neuronal survival and inhibits caspase‐3 activity. However, the mechanisms leading to the opposite regulation of caspase‐3 by C2‐ceramide and PACAP are currently unknown. Here, we show that PACAP prevents C2‐ceramide‐induced inhibition of mitochondrial potential and C2‐ceramide‐evoked cytochrome c release. C2‐ceramide stimulated Bax expression, but had no effect on Bcl‐2, while PACAP abrogated the action of C2‐ceramide on Bax and stimulated Bcl‐2 expression. The effects of C2‐ceramide and PACAP on Bax and Bcl‐2 were blocked, respectively, by the JNK inhibitor L‐JNKI1 and the MEK inhibitor U0126. L‐JNKI1 prevented the alteration of mitochondria induced by C2‐ceramide while U0126 suppressed the protective effect of PACAP against the deleterious action of C2‐ceramide on mitochondrial potential. Moreover, L‐JNKI1 inhibited the stimulatory effect of C2‐ceramide on caspase‐9 and ‐3 and prevented C2‐ceramide‐induced cell death. U0126 blocked PACAP‐induced Bcl‐2 expression, abrogated the inhibitory effect of PACAP on ceramide‐induced caspase‐9 activity, and promoted granule cell death. The present study reveals that C2‐ceramide and PACAP exert opposite effects on Bax and Bcl‐2 through, respectively, JNK‐ and ERK‐dependent mechanisms. These data indicate that the mitochondrial pathway plays a pivotal role in the pro‐ and anti‐apoptotic effects of C2‐ceramide and PACAP.