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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 viaN-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 mmKCl) 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 mmKCl 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.