Sodium channel activation augments NMDA receptor function and promotes neurite outgrowth in immature cerebrocortical neurons

Joju George, Shashank M. Dravid, Anand Prakash, Jun Xie, Jennifer Peterson, Sairam V. Jabba, Daniel G. Baden, Thomas F. Murray

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


A range of extrinsic signals, including afferent activity, affect neuronal growth and plasticity. Neuronal activity regulates intracellular Ca 2+, and activity-dependent calcium signaling has been shown to regulate dendritic growth and branching (Konur and Ghosh, 2005). NMDA receptor (NMDAR) stimulation of Ca 2+/calmodulin-dependent protein kinase signaling cascades has, moreover, been demonstrated to regulate neurite/axonal outgrowth (Wayman et al., 2004). We used a sodium channel activator, brevetoxin (PbTx-2), to explore the relationship between intracellular [Na +] and NMDAR-dependent development. PbTx-2 alone, at a concentration of 30 nM, did not affect Ca 2+ dynamics in 2 d in vitro cerebrocortical neurons; however, this treatment robustly potentiated NMDA-induced Ca 2+ influx. The 30 nM PbTx-2 treatment produced a maximum [Na +] i of 16.9 ±1.5 mM, representing an increment of 8.8 ± 1.8 mM over basal. The corresponding membrane potential change produced by 30 nM PbTx-2 was modest and, therefore, insufficient to relieve the voltage-dependent Mg 2+ block of NMDARs. To unambiguously demonstrate the enhancement of NMDA receptor function by PbTx-2, we recorded single-channel currents from cell-attached patches. PbTx-2 treatment was found to increase both the mean open time and open probability of NMDA receptors. These effects of PbTx-2 on NMDA receptor function were dependent on extracellular Na + and activation of Src kinase. The functional consequences of PbTx-2-induced enhancement of NMDAR function were evaluated in immature cerebrocortical neurons. PbTx-2 concentrations between 3 and 300 nM enhanced neurite outgrowth. Voltage-gated sodium channel activators may accordingly represent a novel pharmacologic strategy to regulate neuronal plasticity through an NMDA receptor and Src family kinase-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)3288-3301
Number of pages14
JournalJournal of Neuroscience
Issue number10
StatePublished - Mar 11 2009

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)


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