1. Opposite regulation of the mitochondrial apoptotic pathway by C2-ceramide and PACAP through a MAP-kinase-dependent mechanism in cerebellar granule cells
- Author
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Falluel-Morel, Anthony, Aubert, Nicolas, Vaudry, David, Basille, Magali, Fontaine, Marc, Fournier, Alain, Vaudry, Hubert, Gonzalez, Bruno J, Neuroendocrinologie cellulaire et moléculaire, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Defense Proteins in Immune and Inflammatory Responses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Faculty of Medicine and Pharmacy-European Institute for Peptide Research-Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), and This research was supported by an INSERM Grant (U413) and an IREB Grant (2001/22). AFM is recipient of a fellowship from the Conseil Re ́gional de Haute-Normandie (LARC-Neuroscience net- work). NA is a recipient of a fellowship from the Conseil Régional de Haute-Normandie and the CIT-IFM Recherche.
- Subjects
MESH: Signal Transduction ,Time Factors ,MAP Kinase Kinase 4 ,MESH: Drug Interactions ,MESH: Neurons ,Fluorescent Antibody Technique ,MESH: Neurotransmitter Agents ,MESH: Neuropeptides ,MESH: Caspase 9 ,MESH: Animals, Newborn ,MESH: Dose-Response Relationship, Drug ,Membrane Potentials ,Mice ,Cytosol ,MESH: Cytosol ,Sphingosine ,MESH: Reverse Transcriptase Polymerase Chain Reaction ,Cerebellum ,MESH: Caspase 3 ,MESH: Animals ,Drug Interactions ,Enzyme Inhibitors ,MESH: Fluorescent Antibody Technique ,Cells, Cultured ,bcl-2-Associated X Protein ,Neurons ,Neurotransmitter Agents ,Caspase 3 ,Reverse Transcriptase Polymerase Chain Reaction ,Intracellular Signaling Peptides and Proteins ,Cytochromes c ,MESH: Cytochromes c ,Carbocyanines ,MESH: Gene Expression Regulation ,Caspase 9 ,Mitochondria ,ERK ,Proto-Oncogene Proteins c-bcl-2 ,MESH: Enzyme Inhibitors ,[SDV.TOX]Life Sciences [q-bio]/Toxicology ,Caspases ,Pituitary Adenylate Cyclase-Activating Polypeptide ,MESH: Carbocyanines ,MESH: Sphingosine ,Mitogen-Activated Protein Kinases ,hormones, hormone substitutes, and hormone antagonists ,MESH: MAP Kinase Kinase 4 ,MESH: Cells, Cultured ,Signal Transduction ,endocrine system ,MESH: Rats ,MESH: Mitochondria ,Blotting, Western ,Models, Neurological ,MESH: Mitogen-Activated Protein Kinase Kinases ,mitochondrial apoptotic pathway ,MESH: Models, Neurological ,MESH: Intracellular Signaling Peptides and Proteins ,MESH: Membrane Potentials ,MESH: Blotting, Western ,Animals ,Bcl-2 ,MESH: bcl-2-Associated X Protein ,Nerve Growth Factors ,RNA, Messenger ,Rats, Wistar ,MESH: Mice ,MESH: RNA, Messenger ,Mitogen-Activated Protein Kinase Kinases ,MESH: Caspases ,Dose-Response Relationship, Drug ,MESH: Nerve Growth Factors ,MESH: Pituitary Adenylate Cyclase-Activating Polypeptide ,MESH: Time Factors ,Neuropeptides ,JNK Mitogen-Activated Protein Kinases ,MESH: JNK Mitogen-Activated Protein Kinases ,MESH: Rats, Wistar ,MESH: Mitogen-Activated Protein Kinases ,MESH: Cerebellum ,Rats ,MESH: Proto-Oncogene Proteins c-bcl-2 ,Animals, Newborn ,Gene Expression Regulation ,Bax ,Benzimidazoles ,JNK ,MESH: Benzimidazoles - Abstract
International audience; 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.
- Published
- 2004
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