Endothelin increases expression of exon III- and exon IV-containing brain-derived neurotrophic factor transcripts in...

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.