Differential Activation of Brain-derived Neurotrophic Factor Gene Promoters I and III by Ca2+ Signals Evoked vial-type Voltage-dependent andN-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<i>N</i>-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.