title: Excitatory GABA induces BDNF transcription via CRTC1 and phosphorylated CREB-related pathways in immature cortical cells.
abstract: Although the excitatory action of GABA has been shown to activate the expression of brain-derived neurotrophic factor (BDNF), its molecular mechanisms remain unclear. Using cultured rat cortical cells, we here demonstrated that GABA induced Bdnf mRNA expression mainly via L-type voltage-dependent Ca(2+) channels (L-VDCC) at the early stage and inhibited it at the late stage of the culture, which corresponded to the excitatory and inhibitory states of cortical cells. The excitatory GABA-induced Bdnf mRNA expression was controlled by multiple Ca(2+) signaling pathways including Ca(2+) /calmodulin-dependent protein kinase (CaMK), mitogen-activated protein kinase (MAPK) and calcineurin (CN). The Bdnf-promoter IV (Bdnf-pIV) was activated by GABA, mainly via cAMP-response element (CRE)/CREB, and this was prevented by the over-expression of a dominant negative CREB. The nuclear translocation of CREB-regulated transcriptional coactivator 1 (CRTC1) was selectively induced by the GABA-induced CN pathway to activate Bdnf-pIV. On the other hand, GABA-induced Gal4-CREB-dependent transcription, which was controlled by multiple Ca(2+) signaling pathways, was prevented when the serine at position 133 of Gal4-CREB was mutated to alanine. Taken together, the excitatory action of GABA transcriptionally activated Bdnf expression through the combination of nuclear-localized CRTC1 and phosphorylated CREB in immature cortical cells, and may be the molecular mechanisms underlying Bdnf expression to control neuronal development. We demonstrated that GABA induced Bdnf expression at the early stage of the culture, in which GABA exerted its excitatory action. The excitatory GABA-induced Bdnf expression was controlled by multiple Ca(2+) signaling pathways evoked via L-VDCC. Both the CREB coactivator, CRTC1 and CREB phosphorylation participated in excitatory GABA-induced Bdnf transcription. Our present study indicates the mechanism underlying the excitatory GABA-induced Bdnf expression in immature neurons and provide new insights into molecular mechanisms underlying Bdnf expression to control neuronal development.
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors: Mamoru
authors: M
authors: Fukuchi
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors: Yuya
authors: Y
authors: Kirikoshi
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors: Atsumi
authors: A
authors: Mori
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors: Reika
authors: R
authors: Eda
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors: Daisuke
authors: D
authors: Ihara
authors: Division of Molecular Genetics Research, Life Science Research Center, University of Toyama, Toyama, Japan.|Department of Pharmacology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan.
authors: Ichiro
authors: I
authors: Takasaki
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors: Akiko
authors: A
authors: Tabuchi
authors: Department of Biological Chemistry, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors: Masaaki
authors: M
authors: Tsuda
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D005680:gamma-Aminobutyric Acid
keywords: BDNF; CREB; CRTC1; Ca2+ signal; GABA