Abstract
Abstract only Brevetoxins (PbTx) are potent polyether neurotoxins that activate voltage‐gated sodium channels. Inasmuch as [Na + ] i has been shown to act as a positive regulator of NMDA receptor currents, we used immature cerebrocortical cultures to assess the influence PbTx‐2 on NMDA receptor mediated calcium influx, excitotoxicity and neurite outgrowth. We first confirmed that PbTx‐2 elevates [Na + ] i in cerebrocortical neurons. PbTx‐2 produced a concentration‐dependent elevation of [Na + ] i in DIV 2, 4, 6 and 9 cerebrocortical cultures. PbTx‐2 (30 nM) leftward shifted the NMDA‐induced Ca 2+ influx concentration‐response curves in cortical cultures. NMDA‐induced excitotoxicity in DIV 4, 6, and 9, but not DIV 2, cerebrocortical cultures was also enhanced by PbTx‐2. The most striking PbTx‐2 potentiation of NMDA‐induced [Ca 2+ ] i elevation occurred in DIV 2 cultures. We used the specific Src kinase inhibitor PP2 to demonstrate that PbTx‐2 potentiation of NMDA‐induced elevation of [Ca 2+ ] i was dependent on Src. Pharmacological studies showed that the PbTx‐2 enhanced neurite outgrowth involves elevation of [Na + ] i , enhancement of NMDA receptor signaling and engagement of the CaMKK pathway.