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Volume 17, Number 11, Issue of June 1, 1997 pp. 4201-4211
Copyright ©1997 Society for NeuroscienceNeurotrophins Protect Cultured Cerebellar Granule Neurons against the Early Phase of Cell Death by a TwoComponent Mechanism
Received Jan. 31, 1997; revised March 17, 1997; accepted March 25, 1997.
Michael J. Courtney, Karl E. O. Åkerman, and Eleanor T. Coffey Department of Biochemistry and Pharmacy, Åbo Akademi University, BioCity, Turku, Finland
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 p75NTR 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 p75NTR 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.
Key words: NGF; BDNF; TNF; neurotrophins; p75NTR; TrkB; cell death; cerebellar granule neurons; PK-C
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