title: Tricyclic antidepressant amitriptyline activates fibroblast growth factor receptor signaling in glial cells: involvement in glial cell line-derived neurotrophic factor production.
abstract: Recently, both clinical and animal studies demonstrated neuronal and glial plasticity to be important for the therapeutic action of antidepressants. Antidepressants increase glial cell line-derived neurotrophic factor (GDNF) production through monoamine-independent protein-tyrosine kinase, extracellular signal-regulated kinase (ERK), and cAMP responsive element-binding protein (CREB) activation in glial cells (Hisaoka, K., Takebayashi, M., Tsuchioka, M., Maeda, N., Nakata, Y., and Yamawaki, S. (2007) J. Pharmacol. Exp. Ther. 321, 148-157; Hisaoka, K., Maeda, N., Tsuchioka, M., and Takebayashi, M. (2008) Brain Res. 1196, 53-58). This study clarifies the type of tyrosine kinase and mechanism of antidepressant-induced GDNF production in C6 glioma cells and normal human astrocytes. The amitriptyline (a tricyclic antidepressant)-induced ERK activation was specifically and completely inhibited by fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors and siRNA for FGFR1 and -2. Treatment with amitriptyline or several different classes of antidepressants, but not non-antidepressants, acutely increased the phosphorylation of FGFRs and FGFR substrate 2α (FRS2α). Amitriptyline-induced CREB phosphorylation and GDNF production were blocked by FGFR-tyrosine kinase inhibitors. Therefore, antidepressants activate the FGFR/FRS2α/ERK/CREB signaling cascade, thus resulting in GDNF production. Furthermore, we attempted to elucidate how antidepressants activate FGFR signaling. The effect of amitriptyline was inhibited by heparin, non-permeant FGF-2 neutralizing antibodies, and matrix metalloproteinase (MMP) inhibitors. Serotonin (5-HT) also increased GDNF production through FGFR2 (Tsuchioka, M., Takebayashi, M., Hisaoka, K., Maeda, N., and Nakata, Y. (2008) J. Neurochem. 106, 244-257); however, the effect of 5-HT was not inhibited by heparin and MMP inhibitors. These results suggest that amitriptyline-induced FGFR activation might occur through an extracellular pathway, in contrast to that of 5-HT. The current data show that amitriptyline-induced FGFR activation might occur by the MMP-dependent shedding of FGFR ligands, such as FGF-2, thus resulting in GDNF production.
authors.affiliation: Division of Psychiatry and Neuroscience, Institute for Clinical Research, 3-1 Aoyama, Kure 737-0023, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Hisaoka
authors.forename: Mami
authors.initials: M
authors.lastname: Tsuchioka
authors.forename: Ryoya
authors.initials: R
authors.lastname: Yano
authors.forename: Natsuko
authors.initials: N
authors.lastname: Maeda
authors.forename: Naoto
authors.initials: N
authors.lastname: Kajitani
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Morioka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakata
authors.forename: Minoru
authors.initials: M
authors.lastname: Takebayashi
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009457:Neuroglia / Q000166:cytology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000929:Antidepressive Agents, Tricyclic; D051100:Glial Cell Line-Derived Neurotrophic Factor; D017468:Receptors, Fibroblast Growth Factor; D000639:Amitriptyline; D012701:Serotonin; D011505:Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases