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.
Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan.
Mamoru
M
Fukuchi
Hiroaki
H
Fujii
Haruna
H
Takachi
Hiroshi
H
Ichinose
Yuki
Y
Kuwana
Akiko
A
Tabuchi
Masaaki
M
Tsuda
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