Voltage-dependent calcium channel involvement in NMDA-induced activation of NOS

We have previously shown that N-methyl-D-aspartate (NMDA) increases nitric oxide synthase (NOS) activity in rat frontal cortex; however, the actual mechanism of this activation has not been addressed. Tetrodotoxin (TTX; 0.05 µM) inhibited NMDA-activated NOS, suggesting that TTX-sensitive Na⁺ channels are interposed between the NMDA receptors and the NOS cellular compartment. The NMDA response was also blocked by voltage-dependent Ca²⁺ channel (VDCC) blockers including Cd²⁺, Co²⁺, funnel web spider toxin (FTX) and w-Aga IVa, but not by nifedipine or w-conotoxin. These data suggest that Ca2+ flux through P- and/or Q-type VDCC subsequent to NMDA-induced depolarization may be at least as important for NOS activation as Ca²⁺ entry through the NMDA receptor.