Differential signaling of glial cell line-derived neurothrophic factor and brain-derived neurotrophic factor in cultured ventral mesencephalic neurons.
In the ventral mesencephalon, two neurotrophic factors, brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, have been shown previously to have similar effects on the survival of dopaminergic neurons. Here, we compared the signaling mechanisms for brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, focusing on the 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 neurotrophic factor and brain-derived neurotrophic factor, c-RET and TrkB, suggesting that they are responsive to both brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Although both brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor induced 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 phosphorylation of mitogen-associated protein kinase by glial cell line-derived neurotrophic factor was transient; within 2 h, the level of mitogen-associated protein 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 neurotrophic factor treatment. PD098059, a specific inhibitor for mitogen-associated protein kinase kinase, completely blocked the glial cell line-derived neurotrophic factor signaling through mitogen-associated protein kinase, but had no effect on brain-derived neurotrophic factor-induced mitogen-associated protein kinase phosphorylation. Both brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor induced the phosphorylation of cyclic-AMP responsive element-binding protein in the nuclei of ventral mesencephalon neurons. However, PD098059 blocked the cyclic-AMP responsive element-binding protein phosphorylation induced by glial cell line-derived neurotrophic factor, but not that by brain-derived neurotrophic factor. These results indicate that, although both brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor act on ventral mesencephalon neurons, the two factors have different signaling mechanisms, which may mediate their distinctive biological functions.
Feng
L
L
Unit on Synapse Development and Plasticity, Laboratory of Developmental Neurobiology, NICHD, NIH, Bethesda, MD 20892-4480, USA.
Wang
C Y
CY
Jiang
H
H
Oho
C
C
Dugich-Djordjevic
M
M
Mei
L
L
Lu
B
B
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry; D008636:Mesencephalon / Q000166:cytology / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009414:Nerve Growth Factors / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009457:Neuroglia / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D005419:Flavonoids; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one