Abstract
Brevetoxins (PbTx) are potent polyether neurotoxins that activate voltage‐gated sodium channels (VGSC) and indirectly augment NMDA receptor‐mediated Ca2+ signaling in neocortical neurons. We have characterized the effects of subtoxic concentrations of PbTx‐2 on neurite growth of immature murine cerebral cortical neurons. PbTx‐2 concentration‐response experiments showed that 30nM PbTx‐2 was most effective in stimulating neurite growth in immature neurons following exposures of 15–108h. Furthermore, we found that the VGSC antagonist, tetrodotoxin, blocked PbTx‐2‐induced neurite growth, indicating that the PbTx‐2 response is mediated by activation of VGSCs. STO‐609, an inhibitor of CaM‐dependent protein kinase kinase (CaMKK), also blocked the PbTx‐2 enhanced neurite growth. This suggests that the PbTx‐2 triggered neuronal growth mechanism involves a Ca2+‐dependent CaMKK pathway. The NMDA receptor antagonist MK801 similarly inhibited PbTx‐2‐induced neurite growth. These results indicate that PbTx‐2 induced neurite growth is dependent on NMDA receptor mediated Ca2+ entry with subsequent activation of a Ca2+ dependent CaMKK pathway. Considered together these data suggest that brevetoxin enhancement of neuronal growth sequentially involves an increase in Na+ influx, upregulation of NMDA receptor signaling, and engagement of the Ca2+ dependent CaMKK pathway.