Heparin facilitates glial cell line-derived neurotrophic factor signal transduction.
Glial cell-line neurotrophic factor (GDNF), a neurotrophic factor with heparin binding affinity, promotes the survival and differentiation of a variety of neuronal cells including dopaminergic neuron. The effect of heparin on GDNF signaling was investigated based on the expression of the tyrosine hydroxyrase (TH) gene in neurobalstoma cells. Up-regulation of TH gene mRNA by GDNF was enhanced by co-administration of heparin. This facilitation by heparin was particularly evident at suboptimal levels of GDNF, which was consistent with the luciferase assay using TH gene promoter. Pretreatment with heparitinase decreased TH promoter activity in the absence of heparin. Phosphorylation of extracellular regulated kinase was increased in the presence of heparin, although tyrosine phosphorylation of Ret receptor tyrosine kinase was not affected by heparin. Expression of early response genes such as c-fos or Egr1 increased and sustained in the presence of heparin more than that without heparin. These results indicate that interaction with glycosaminoglycans such as heparin affects GDNF signal transduction positively.
Tanaka
Mikiei
M
Laboratory for Genes of Motor Systems, Bio-Mimetic Control Research Program, The Institute of Physical and Chemical Research (RIKEN), Nagoya, Japan.
Xiao
Hengyi
H
Kiuchi
Kazutoshi
K
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D048429:Cell Size / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D004347:Drug Interactions / Q000502:physiology; D017781:Genes, Immediate-Early / Q000187:drug effects / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006493:Heparin / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics; D009414:Nerve Growth Factors / Q000187:drug effects* / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011133:Polysaccharide-Lyases / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D029721:Drosophila Proteins; C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D006493:Heparin; D014446:Tyrosine 3-Monooxygenase; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C495001:Ret protein, rat; D020928:Mitogen-Activated Protein Kinases; D011133:Polysaccharide-Lyases; C021349:heparitinsulfate lyase; D004298:Dopamine