Differential activation of brain-derived neurotrophic factor gene promoters I and III by Ca2+ signals evoked via L-type voltage-dependent and N-methyl-D-aspartate receptor Ca2+ channels

Abstract

Although the brain-derived neurotrophic factor (BDNF) gene is activated by the intracellular Ca2+ signals evoked via Ca2+ influx into neurons, little is known about how the activation of alternative BDNF gene promoters is controlled by the Ca2+ signals evoked via N-methyl-D-aspartate receptors (NMDA-R) and L-type voltage-dependent Ca2+ channels (L-VDCC). There is a critical range in the membrane depolarization caused by high K+ concentrations (25-50 mM KCl) for effective BDNF mRNA expression and transcriptional activation of BDNF gene promoters I and III (BDNF-PI and - PIII, respectively) in rat cortical culture. The increase in BDNF mRNA expression induced at high K+ was repressed not only by nicardipine, an antagonist for L-VDCC, but also by DL-amino-5-phosphonovalerate, an antagonist for NMDA-R, which was supported by the effects of antagonists on the Ca2+ influx. Although the promoter activations at 25 and 50 mM KCl were different, BDNF-PIII was activated by either the Ca2+ influx through NMDA-R or L-VDCC, whereas BDNF-PI was predominantly by the Ca2+ influx through L- VDCC. Direct stimulation of NMDA-R supported the activation of BDNF-PIII but not that of BDNF-PI. Thus, the alternative BDNF gene promoters responded differently to the intracellular Ca2+ signals evoked via NMDA-R and L-VDCC.