title: Sphingosine induces apoptosis in hippocampal neurons and astrocytes by activating caspase-3/-9 via a mitochondrial pathway linked to SDK/14-3-3 protein/Bax/cytochrome c.
abstract: The present study examined sphingosine-induced apoptosis in cultured rat hippocampal neurons and astrocytes. Sphingosine induced apoptosis in a concentration (1-100 µM)-dependent manner, that is inhibited by the PKC-δ inhibitor rottlerin, and a similar effect was obtained with the sphingosine kinase inhibitors, to raise intracellular sphingosine concentrations. Sphingosine increased presence of sphingosine-dependent protein kinase (SDK), and the effect was suppressed by rottlerin. Sphingosine increased phosphorylated 14-3-3 protein, thereby transforming the protein from a dimeric structure into a monomeric structure. Sphingosine accumulated Bax in the mitochondria and stimulated cytochrome c release into the cytosol, and those effects were inhibited by rottlerin. Sphingosine disrupted mitochondrial membrane potentials, that was abolished by silencing the PKC-δ-targeted gene. Moreover, sphingosine activated caspase-9 and the effector caspase-3 in a PKC-δ-dependent manner. Taken together, the results of the present study indicate that sphingosine activates SDK, produced through proteolytic processing of an active form of PKC-δ, to phosphorylate 14-3-3 protein and transform into a monomeric structure, causing Bax dissociation from 14-3-3 protein and accumulation in the mitochondria, which perturbs mitochondrial membrane potentials allowing cytochrome c release into the cytosol, to activate caspase-9 and the effector caspase-3, responsible for apoptosis in hippocampal neurons and astrocytes.
authors.affiliation: Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanno
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Nishizaki
mesh_terms: D048948:14-3-3 Proteins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D053148:Caspase 3 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D055503:Protein Multimerization; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D048948:14-3-3 Proteins; D053148:Caspase 3; D053453:Caspase 9; D045304:Cytochromes c; D017853:Phosphotransferases (Alcohol Group Acceptor); D051745:Protein Kinase C-delta; D013110:Sphingosine; D013844:Thiazoles; D051028:bcl-2-Associated X Protein; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol