5-HT2A receptor activation leads to increased BDNF mRNA expression in C6 glioma cells.
It has recently been suggested that an increase in brain-derived neurotrophic factor (BDNF) expression may mediate some of the therapeutic effect of antidepressant drugs, via their effects on the neurotransmitter 5-hydroxytryptamine (5-HT). However, because it is unclear whether 5-HT manipulations directly affect BDNF expression, we examined BDNF mRNA levels in C6 glioma cells following incubation with 5-HT using reverse transcription polymerase chain reaction (RT-PCR) and Northern blot analysis. Incubation of C6 glioma cells with 5-HT increased the BDNF mRNA expression approx twofold. The effect of 5-HT (100 microM) was inhibited by a 5-HT2A receptor antagonist (ketanserin; 1 microM). The RNA synthesis inhibitor (actinomycin D; 10 microg/mL), but not a protein synthesis inhibitor (cycloheximide; 0.5 microg/mL) blocked the effect of 5-HT. Furthermore, incubation of C6 glioma cells with EGTA (1 mM), a protein kinase inhibitor (staurosporine; 1 microM), the Ca2+ ATPase inhibitor thapsigargin (1 microM), or a calcium/calmodulin-dependent kinase inhibitor (KN 62; 1 microM) inhibited the response to 5-HT. Our data show that 5-HT increases de novo BDNF mRNA synthesis following direct activation of the 5-HT2A receptor, via a calcium-dependent and protein kinase-dependent pathway.
Meller
Robert
R
Smithkline Beecham Centre for Applied Neuropsychobiology, University Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford. rmeller@downneurobiology.org
Babity
Joseph M
JM
Grahame-Smith
David G
DG
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D019384:Nucleic Acid Synthesis Inhibitors; D011494:Protein Kinases; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors