Serotonin (5-HT) induces glial cell line-derived neurotrophic factor (GDNF) mRNA expression via the transactivation of fibroblast growth factor receptor 2 (FGFR2) in rat C6 glioma cells.
We previously reported that serotonin (5-HT) increased glial cell line-derived neurotrophic factor (GDNF) release in a 5-HT(2) receptor (5-HT(2)R) and mitogen-activated protein kinase kinase/extracellular signal-related kinase (MEK/ERK)-dependent manner in rat C6 glioma cells (C6 cells), a model of astrocytes. We herein found that 5-HT-induced rapid ERK phosphorylation was blocked by 5-HT(2)R antagonists in C6 cells. We therefore examined 5-HT-induced ERK phosphorylation to reveal the mechanism of 5-HT-induced GDNF mRNA expression. As 5-HT-induced ERK phosphorylation was blocked by inhibitors for Galpha(q/11) and fibroblast growth factor receptor (FGFR), but not for second messengers downstream of Galpha(q/11), 5-HT(2)R-mediated FGFR transactivation was suggested to be involved in the ERK phosphorylation. Although FGFR1 and 2 were functionally expressed in C6 cells, 5-HT selectively phosphorylated FGFR2. Indeed, small interfering RNA for FGFR2, but not for FGFR1, blocked 5-HT-induced ERK phosphorylation. As Src family tyrosine kinase inhibitors and microtubule depolymerizing agents blocked 5-HT-induced FGFR2 phosphorylation, Src family tyrosine kinase and stabilized microtubules were suggested to act upstream of FGFR2. Finally, 5-HT-induced GDNF mRNA expression was also inhibited by the blockade of 5-HT(2)R, FGFR, and Src family tyrosine kinase. In conclusion, our findings suggest that 5-HT induces GDNF mRNA expression via 5-HT(2)R-mediated FGFR2 transactivation in C6 cells.
Tsuchioka
Mami
M
Division of Psychiatry and Neuroscience, Institute of Clinical Research, National Hospital Organization (NHO), Kure Medical Center and Chugoku Cancer Center, Kure, Japan.
Takebayashi
Minoru
M
Hisaoka
Kazue
K
Maeda
Natsuko
N
Nakata
Yoshihiro
Y
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D051100:Glial Cell Line-Derived Neurotrophic Factor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; D012701:Serotonin; C496356:Fgfr2 protein, rat; D051497:Receptor, Fibroblast Growth Factor, Type 2; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11