Brain-derived Neurotrophic Factor Enhances Neuronal Translation by Activating Multiple Initiation Processes

Abstract

The effects of neurotrophic factors on translational activation were investigated in cortical neurons. Brainderived neurotrophic factor (BDNF) increased protein synthesis within 30 min, whereas insulin produced a weaker enhancement of protein synthesis. BDNF-triggered protein synthesis was inhibited by LY294002, PD98059, and rapamycin, whereas the effect of insulin was unaffected by PD98059. To explore the mechanisms underlying this effect, the protein phosphorylation cascades that lead to the activation of translation initiation in neurons were examined. BDNF induced the phosphorylation of both eukaryote initiation factor (eIF) 4E and its binding protein (eIF4E-binding protein-1). The former reaction was inhibited by PD98059, whereas the latter was inhibited by LY294002 or rapamycin. In agreement, BDNF induced the phosphorylation of mammalian TOR (target of rapamycin) and enhanced its kinase activity toward eIF4E-binding protein-1. In contrast, insulin failed to activate MAPK and did not induce the phosphorylation of eIF4E. Since BDNF and insulin increased the activity of eIF2B and eIF2, the only difference between them was eIF4E phosphorylation. Thus, this may explain the lower activity of insulin in potentiating neuronal protein synthesis. These results suggest strongly that BDNF simultaneously activates multiple signaling cascades consisting of phosphatidylinositol 3-kinase, mammalian TOR, and MAPK to enhance translation initiation in neurons.

Transforming Growth Factor-α Attenuates N-Methyl-D-aspartic Acid Toxicity in Cortical Cultures by Preventing Protein Synthesis Inhibition through an Erk1/2-dependent Mechanism

“…eIF4E was shown to play a pivotal role in the activation of translation by epidermal growth factor and nerve growth factor in PC12 cells after nutrient deprivation (23). In cortical cultures, brain-derived neurotrophic factor is a better stimulator of protein synthesis than insulin because it phosphorylates eIF4E, whereas insulin does not (25). In a similar manner, eIF4E phosphorylation by TGF-␣ might be involved in the recovery of protein synthesis after NMDA exposure.…”

“…Under the phosphorylated state, they dissociate from eIF4E and no longer block the complex formation. The mammalian target of rapamycin, a downstream kinase of Akt (18), is the enzyme responsible for eIF4E-BP phosphorylation in cortical neurons (25). Many growth factors, such as IGF-1 (26), brain-derived neurotrophic factor (25), and epidermal growth factor (55) activate the mammalian target of rapamycin and phosphorylate eIF4E-BP.…”

“…The mammalian target of rapamycin, a downstream kinase of Akt (18), is the enzyme responsible for eIF4E-BP phosphorylation in cortical neurons (25). Many growth factors, such as IGF-1 (26), brain-derived neurotrophic factor (25), and epidermal growth factor (55) activate the mammalian target of rapamycin and phosphorylate eIF4E-BP. However, because TGF-␣ did not activate Akt signaling pathway in our cultures, we assume that eIF4E-BP did not play a major role in the regulation of eIF4E.…”

Translational Control via the Mammalian Target of Rapamycin Pathway Is Critical for the Formation and Stability of Long-Term Fear Memory in Amygdala Neurons

“…Rapamycin-sensitive signaling has been shown to be involved in BDNF-mediated activation of translational factors and increases in selected proteins. Takei et al (2001) showed that BDNF induces the expression of phospho-4E-BP1 and phospho-eIF4E in cortical neurons, and that this effect can be blocked by RAP. A related study found that RAP also attenuated the BDNF-induced expression of Arc and CamkII protein in cortical neurons (Takei et al, 2004).…”

Effects of rapamycin on gene expression, morphology, and electrophysiological properties of rat hippocampal neurons

“…In fact, no study has documented effects of rapamycin on neuronal gene transcription. Rapamycin mediates protein synthesis stimulated by brain derived neurotrophic factor (Takei et al, 2001;Schratt et al, 2004). Rapamycin has also been shown to have direct neurophysiological effects, although some of the data have been controversial.…”