BDNF-mediated signal transduction is modulated by GSK3beta and mood stabilizing agents.
Brain-derived neurotrophic factor (BDNF) is a major neurotrophin in the brain and abnormal regulation of BDNF may contribute to the pathophysiology of mood disorders. In the present study, we examined if alterations in the activity of glycogen synthase kinase-3-beta (GSK3beta) or treatment with mood stabilizers modulated BDNF-mediated signal transduction pathways in differentiated human neuroblastoma SH-SY5Y cells. BDNF increased the phosphorylation of the forkhead transcription factor FKHRL1 through activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, and the phosphorylation of the cyclic AMP response element binding protein (CREB) through activation of extracellular signal-regulated kinase1/2 (ERK1/2). BDNF also increased serine(9) -phosphorylation of GSK3beta, which inhibits GSK3beta activity. Overexpression of GSK3beta did not affect BDNF-induced phosphorylation of Akt, ERK1/2, or FKHRL1, but abolished CREB phosphorylation induced by BDNF. This inhibition of BDNF-induced CREB phosphorylation in GSK3beta-overexpressing SH-SY5Y cells was blocked by treatment with lithium. In contrast to lithium, sodium valproate and lamotrigine did not affect BDNF-mediated signaling, whereas carbamazepine induced a rapid and prolonged phosphorylation of ERK1/2 and CREB in the absence or the presence of BDNF. Therefore, increased GSK3beta selectively attenuates BDNF-induced CREB phosphorylation, and lithium and carbamazepine can facilitate activation of CREB.
Mai
Lian
L
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 1075 Sparks Center, 1720 7th Avenue South, Birmingham, AL 35294-00017, USA.
Jope
Richard S
RS
Li
Xiaohua
X
D000927:Anticonvulsants / Q000494:pharmacology; D018692:Antimanic Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D008094:Lithium / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000927:Anticonvulsants; D018692:Antimanic Agents; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014212:Tretinoin; D008094:Lithium; D038341:Glycogen Synthase Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3