Endothelin increases expression of exon III- and exon IV-containing brain-derived neurotrophic factor transcripts in cultured astrocytes and rat brain.
The effects of endothelins (ETs) on brain-derived neurotrophic factor (BDNF) production in astrocytes were investigated. ET-1 (100 nM) increased the mRNA level and extracellular release of BDNF in cultured astrocytes. RT-PCR analyses using primer pairs that amplified exon-specific BDNF transcripts revealed that exon III- and exon IV-containing BDNF transcripts existed in cultured astrocytes, whereas exon I- and exon II-containing BDNF transcripts did not. ET-1 and Ala(1,3,11,15)-ET-1, an ET(B) receptor agonist, increased the expressions of the exon III and exon IV transcripts in cultured astrocytes. Intracerebroventricular administration of 500 pmol/day of Ala(1,3,11,15)-ET-1 increased exon III and exon IV BDNF transcripts in the rat striatum. In cultured astrocytes, Ca(2+)-chelation, W-7 (a calmodulin inhibitor), and KN93 (a Ca(2+)/calmodulin kinase inhibitor) inhibited the increases in exon IV BDNF mRNA and CCAAT enhancer-binding protein beta (C/EBPbeta) levels induced by ET-1. The ET-induced increases in exon III BDNF mRNA expression and phosphorylation of cAMP response element binding protein (CREB) were reduced by Ca(2+) chelation, W-7, KN93, PD98059 (a MEK inhibitor), and wortmannin (a phosphatidylinositol 3-kinase inhibitor). These results suggest that ETs stimulate the expressions of exon III and exon IV BDNF transcripts in astrocytes through CREB and C/EBPbeta-mediated mechanisms, respectively.
Koyama
Yutaka
Y
Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan. koyama@phs.osaki-u.ac.jp
Tsujikawa
Kimiko
K
Matsuda
Toshio
T
Baba
Akemichi
A
D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000187:drug effects*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D016232:Endothelins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons; D015870:Gene Expression / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D012322:RNA Precursors / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D022782:CCAAT-Enhancer-Binding Protein-beta; D017362:Cyclic AMP Response Element-Binding Protein; D016232:Endothelins; D004791:Enzyme Inhibitors; D012322:RNA Precursors; D012333:RNA, Messenger