Neurotrophins protect cultured cerebellar granule neurons against the early phase of cell death by a two-component mechanism.
Cerebellar granule neurons cultured with serum develop a mature neuronal phenotype, including stimulus-coupled release of glutamate, and depend on elevated potassium for survival. We find that cells cultured with serum undergo two phases of cell death. By 6 d in vitro, 30-50% of the cells present are dead; after this time the remaining cells die. Elevated potassium prevents only this later phase of death, whereas neurotrophins protect these cells against the early phase of death. Factors that bind p75(NTR) or TNF-R, members of the same receptor family, exhibit voltage-sensitive calcium channel-dependent protection, whereas ligands of expressed Trk receptors show additional calcium channel-independent protection. The cells express TrkB protein and show elevated c-Fos and c-Jun levels in response to BDNF. No TrkA is detected, although p75(NTR) protein is expressed and NGF induces depolarization-dependent elevation of c-Jun levels. In the presence of the protein kinase C inhibitor bisindolylmaleimide, BDNF-induced survival promotion is reduced partially, whereas NGF-induced death is unmasked. Basal survival mechanisms are insensitive to inhibition of PK-C or PI-3 kinase. We conclude that BDNF promotes survival in part via its TrkB receptor, whereas there is an additional pathway promoting survival and elevating c-Jun evoked by both NGF and BDNF via a non-Trk receptor.
Courtney
M J
MJ
Department of Biochemistry and Pharmacy, Abo Akademi University, BioCity, Turku, Finland.
Akerman
K E
KE
Coffey
E T
ET
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D002531:Cerebellum / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D017781:Genes, Immediate-Early / Q000235:genetics; D016328:NF-kappa B / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D020933:Neurotrophin 3; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D020801:Receptor, Ciliary Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D019208:Brain-Derived Neurotrophic Factor; D002273:Carcinogens; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins; D020801:Receptor, Ciliary Neurotrophic Factor; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D014409:Tumor Necrosis Factor-alpha; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D000077191:Wortmannin