Activation of tyrosine hydroxylase (TH) gene transcription induced by brain-derived neurotrophic factor (BDNF) and its selective inhibition through Ca(2+) signals evoked via the N-methyl-D-aspartate (NMDA) receptor.
Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of catecholamine but its transcriptional regulation is not fully understood. Using a reporter assay with cultured rat cortical neurons, we demonstrated that the TH gene promoter was activated by brain-derived neurotrophic factor (BDNF), through its specific receptor TrkB and the ERK/MAP kinase pathway. Using a series of mutant TH gene promoters, we found that the cAMP-response element (CRE) plays a crucial role in the TH promoter activity and the Egr-1-responsive element (ERE), at least in part, is responsible for the BDNF-induced activation. Notably, the influx of Ca(2+) evoked via the N-methyl-D-aspartate receptor (NMDA-R) but not via the L-type voltage-dependent Ca(2+) channel (L-VDCC) selectively antagonized the activation of the gene promoter, suggesting a new link between the catecholaminergic and glutamatergic systems. The Ca(2+) signals evoked via NMDA-R did not affect the phosphorylation of ERK1/2 induced by BDNF. These results suggest that the TH gene's transcription is positively regulated by BDNF, through the CRE and ERE of the promoter, but selectively antagonized by the Ca(2+) signals evoked via NMDA-R without disturbing the ERK/MAP kinase pathway, the regulation by which may underlie the development of the catecholaminergic system in the brain.
Fukuchi
Mamoru
M
Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
Fujii
Hiroaki
H
Takachi
Haruna
H
Ichinose
Hiroshi
H
Kuwana
Yuki
Y
Tabuchi
Akiko
A
Tsuda
Masaaki
M
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D009154:Mutation / Q000235:genetics; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D009529:Nicardipine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C019277:brain-derived growth factor; D011189:Potassium Chloride; D009529:Nicardipine; D014446:Tyrosine 3-Monooxygenase; D052066:N-Ethylmaleimide-Sensitive Proteins; C498737:Nsf protein, rat