Inhibition of protein phosphatases induces IGF-1-blocked neurotrophin-insensitive neuronal apoptosis.
We have previously described the marine toxin okadaic acid (OKA) to be a potent neurotoxin for cultured rat cerebellar neurons. Here we show that OKA-induced neurodegeneration involves the DNA fragmentation characteristic of apoptosis and is protein synthesis-dependent. DNA fragmentation and neurotoxicity correlated with inhibition of protein phosphatase (PP) 2A rather than PP1 activity. Neurotrophins NT-3 and BDNF failed to protect from OKA-induced apoptotic neurotoxicity that was, however, totally prevented by insulin-like growth factor-1. Neuronal death by OKA was significantly reduced by protein kinase C inhibitors and by the L-type calcium channel agonist Bay K8644, while it was potentiated by the reduction of free extracellular calcium concentrations.
Fernández-Sánchez
M T
MT
Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo, Spain.
García-Rodríguez
A
A
Díaz-Trelles
R
R
Novelli
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009410:Nerve Degeneration / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology; D020933:Neurotrophin 3; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011493:Protein Kinase C / Q000187:drug effects / Q000502:physiology; D051381:Rats
D019208:Brain-Derived Neurotrophic Factor; D002120:Calcium Channel Agonists; D004791:Enzyme Inhibitors; D009414:Nerve Growth Factors; D009498:Neurotoxins; D020933:Neurotrophin 3; D019319:Okadaic Acid; D007334:Insulin-Like Growth Factor I; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases