title: Sodium channel activation augments NMDA receptor function and promotes neurite outgrowth in immature cerebrocortical neurons.
abstract: 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.
authors.affiliation: Department of Pharmacology, Creighton University School of Medicine, Omaha, Nebraska 68178, USA.
authors.forename: Joju
authors.initials: J
authors.lastname: George
authors.forename: Shashank M
authors.initials: SM
authors.lastname: Dravid
authors.forename: Anand
authors.initials: A
authors.lastname: Prakash
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.forename: Jennifer
authors.initials: J
authors.lastname: Peterson
authors.forename: Sairam V
authors.initials: SV
authors.lastname: Jabba
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Baden
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Murray
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development*; D005260:Female; D008387:Marine Toxins / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D035964:Oxocins / Q000494:pharmacology; D011247:Pregnancy; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D062687:Sodium Channel Agonists; D015222:Sodium Channels / Q000378:metabolism*; D000095702:Polyether Toxins
chemical_list: D008387:Marine Toxins; D035964:Oxocins; D016194:Receptors, N-Methyl-D-Aspartate; D062687:Sodium Channel Agonists; D015222:Sodium Channels; C053342:brevetoxin; D000095702:Polyether Toxins