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Neuroprotection of immortalized hippocampal neurones by brain‐derived neurotrophic factor and Raf‐1 protein kinase: role of extracellular signal‐regulated protein kinase and phosphatidylinositol 3‐kinase
Author(s) -
Rössler Oliver G.,
Giehl Klaus M.,
Thiel Gerald
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02255.x
Subject(s) - tropomyosin receptor kinase b , mapk/erk pathway , neuroprotection , neurotrophic factors , microbiology and biotechnology , kinase , glial cell line derived neurotrophic factor , brain derived neurotrophic factor , neurotrophin , programmed cell death , protein kinase a , glutamate receptor , biology , chemistry , neuroscience , receptor , biochemistry , apoptosis
We have investigated the molecular mechanisms of neurotrophin‐mediated cell survival in HT22 cells, a murine cell line of hippocampal origin, expressing the brain‐derived neurotrophic factor (BDNF) receptor TrkB as well as the TrkB.T1 splice variant. Stimulation with BDNF protected HT22‐TrkB cells, but not HT22‐TrkB.T1 cells, against programmed cell death induced by serum deprivation. BDNF did not, however, provide protection against oxidative glutamate toxicity, indicating that serum deprivation‐induced cell death differs substantially from glutamate‐induced cell death. Using a pharmacological strategy to block either the extracellular signal‐regulated protein kinase (ERK) or the phosphatidylinositol 3‐kinase (PI3) pathway, we show that activation of PI3 kinase is required for the neuroprotective activity of BDNF in HT22 cells. To further analyse the role of ERK in neuroprotection we expressed an inducible ΔRaf‐1:ER fusion protein in HT22 cells. Activation of this conditionally active form of Raf‐1 induced a sustained phosphorylation of ERK, and protected the cells from serum withdrawal‐induced cell death. Inhibition of ERK activation at different time points revealed that a prolonged activation of ERK is essential to protect HT22 cells from cell death triggered by the withdrawal of serum, indicating that the duration of ERK activation is of major importance for its neuroprotective biological function.