Role of extracellular signal‐regulated protein kinase and phosphatidylinositol 3‐kinase in neuronal cell death and survival

Abstract

The survival of neurons requires, at some point, the presence of neurotrophic factors and depends on competition for a limited supply of survival factors. The neurotrophin brain-derived neurotrophic factor (BDNF) is the ligand for the TrkB neurotrophin receptor, the most abundant Trk receptor in the brain. Two key signaling pathways are induced following binding of BDNF to its cognate receptor that are characterized by the activation of extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3 kinase). Many reports have assigned a cellular survival function to the activation of ERK and/or PI3 kinase, in line with the reported neuroprotective activity of neurotrophin receptor activation. The activation of PI3 kinase by BDNF represents the dominant survival pathway, whereas the ERK signaling pathway has no or only a marginal role. However, a sustained activation of ERK, lasting for several hours, protects neurons from growth factor deprivation-induced cell death, indicating that the duration of ERK activation is of major importance for its neuroprotective biological function. The activation of ERK and PI3 kinase does not provide protection against oxidative glutamate toxicity. Thus, the biochemical events underlying neuronal cell death induction by the lack of trophic support or via oxidative stress are distinct.