Differential signaling of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor in cultured ventral mesencephalic neurons

In the ventral mesencephalon, two neurotrophic factors, brain-derived neuro trophic factor and glial cell Line-derived neurotrophic factor, have been s hown previously to have similar effects on the survival of dopaminergic neu rons. Here, we compared the signaling mechanisms for brain-derived neurotro phic factor and glial cell line-derived neurotrophic factor, focusing on th e mitogen-associated protein kinase and the transcription factor cyclic-AMP responsive element-binding protein. Double staining experiments indicated that many neurons co-expressed the receptors for glial cell line-derived ne urotrophic factor and brain-derived neurotrophic factor, c-RET and TrkB, su ggesting that they are responsive to both brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Although both brain-deriv ed neurotrophic factor and glial cell line-derived neurotrophic factor indu ced a rapid phosphorylation of mitogen-associated protein kinase and cyclic -AMP responsive element-binding protein, there were significant differences in the kinetics and pharmacology of the phosphorylation. The phosphorylati on of mitogen-associated protein kinase by glial cell line-derived neurotro phic factor was transient; within 2 h, the level of mitogen associated prot ein kinase phosphorylation returned to baseline. In contrast, the effect of brain-derived neurotrophic factor was long lasting: the mitogen-associated protein kinase remained phosphorylated for up to 4 h after brain-derived n eurotrophic factor treatment. PD098059, a specific inhibitor for mitogen-as sociated protein kinase kinase, completely blocked the glial cell Line deri ved neurotrophic factor signaling through mitogen-associated protein kinase , but had no effect on brain-derived neurotrophic factor-induced mitogen-as sociated protein kinase phosphorylation. Both brain-derived neurotrophic fa ctor and glial cell line-derived neurotrophic factor induced the phosphoryl ation of cyclic-AMP responsive element-binding protein in the nuclei of ven tral mesencephalon neurons. However, PD098059 blocked the cyclic-AMP respon sive element-binding protein phosphorylation induced by glial cell line-der ived neurotrophic factor, but not that by brain-derived neurotrophic factor . These results indicate that, although both brain-derived neurotrophic facto r and glial cell line-derived neurotrophic factor act on ventral mesencepha lon neurons, the two factors have different signaling mechanisms, which may mediate their distinctive biological functions.