Brevetoxins (PbTx) are potent allosteric enhancers of voltage-gated sodium channel (VGSC) function and are associated with periodic "red tide" blooms. These neurotoxins produce neuronal injury and death in cerebellar granule cells (CGC) following acute exposure. In murine neocortical neurons, brevetoxin induces Ca(2+) influx that is mediated through both glutamatergic and non-glutamatergic pathways. Inasmuch as Src kinase is capable of upregulating the NMDA subtype of glutamate receptors, we determined whether Src kinase participated in PbTx-2-induced Ca(2+) influx. Inhibition of Src kinase blocked PbTx-2-induced Ca(2+) influx. PbTx-2 treatment moreover increased tyrosine phosphorylation of the NR2B subunit. A rise in intracellular [Na(+)] and phosphorylation of NMDA receptors by Src kinase is known to increase NMDA receptor activity. We therefore explored the influence of brevetoxin on NMDA receptor function. We found that PbTx-2 augments NMDA receptor-mediated Ca(2+) influx in both spontaneously oscillating mature neurons and in non-oscillatory immature neurons. PbTx-2 also enhanced the effect of bath-applied NMDA on extracellular signal-regulated kinase 2 (ERK2) activation. These results suggest that brevetoxin augments NMDA receptor signaling in neocortical neurons, and this upregulation may be mediated by coincidence of an elevation in intracellular [Na(+)] and Src kinase activation.