Extracellular adenosine 5′‐triphosphate elicits the expression of brain‐derived neurotrophic factor exon IV mRNA in rat astrocytes

Abstract

A growing body of recent evidence indicates that ATP plays an important role in neuronal-glial communications. In this study, the authors demonstrated that extracellular ATP elicits the gene expression of brain-derived neurotrophic factor (BDNF), especially BDNF exon IV mRNA, in primary cultured rat cortical astrocytes but not in neurons. To investigate the mechanism by which ATP induces BDNF exon IV mRNA expression, the authors used immortalized astrocyte cell line RCG-12. ATP dose-dependently increased the expression of BDNF exon IV mRNA and activated BDNF promoter IV. P2Y receptor agonists (ADP and 2MeS-ADP) but not a P2X receptor agonist (alphabetaMeATP) induced the expression of BDNF exon IV mRNA. Moreover, ATP-induced BDNF exon IV mRNA upregulation was inhibited by a P2Y antagonist (MRS2179) but not by P2X antagonists (TNP-ATP and PPADS). These findings suggest the involvement of P2Y receptors in the ATP-induced transcription of the BDNF gene. Among the signal transduction inhibiters examined in this study, intracellular Ca(2+) chelator (BAPTA-AM) and Ca(2+)/calmodulin-dependent kinase (CaM kinase) inhibitors (KN-93 and W-7) attenuated ATP-induced BDNF exon IV mRNA upregulation. ATP transiently induced the phosphorylation of cAMP-responsive element-binding protein (CREB). ATP-induced CREB phosphorylation was repressed by P2Y antagonists, BAPTA-AM, and CaM kinase inhibitors. Overexpression of dominant negative CREB mutants reduced the activation of BDNF promoter IV and attenuated the upregulation of BDNF exon IV mRNA expression. These results suggest that ATP induces BDNF expression through P2Y receptor followed by the activation of CaM kinase and CREB in astrocytes. These mechanisms are likely to contribute to the enhancement of neuronal-glial networks.

Severe instead of mild hyperglycemia inhibits neurogenesis in the subventricular zone of adult rats after transient focal cerebral ischemia

“…It is observed that cerebral ischemia raises adenosine triphosphate (ATP) outflow in the striatum (Melani et al, 2005), which elicits the gene expression of BDNF through P2Y receptor followed by the activation of CREB in astrocytes (Takasaki et al, 2008). In accordance with that, our data showed increased p-CREB/GFAP double-positive cells in the normoglycemic and 10 mM groups which indicated that ischemia triggered phosphorylation of CREB in astrocytes.…”

Imipramine Induces Brain-Derived Neurotrophic Factor mRNA Expression in Cultured Astrocytes

“…It is reported that rat BDNF mRNA has multiple different transcripts, which differ in the 5′-promotor regions and that astrocytic BDNF is translated by exon-III-and exon-IV-containing transcripts (28,29). The primers for BDNF mRNA used in the present study could not distinguish these transcripts.…”

“…It has been reported that intracellular Ca 2+ elevation increases BDNF mRNA expression in astrocytes (28). Long-term treatment of imipramine enhances serotoninmediated intracellular Ca 2+ elevation (48).…”

Purinoceptors on Neuroglia

“…Similarly stimulation of metabotropic P2Y receptors increased synthesis of prostaglandins [228]. Activation of P2Y 1 receptors induced expression of brain-derived neurotrophic factor in astroglial cell line [229].…”