Involvement of Phosphoinositide 3‐kinase‐Akt signaling pathway in sodium channel activator‐induced neurite outgrowth

Abstract

Calcium influx through N‐methyl D‐aspartate receptors (NMDAR) regulates signaling cascades that underlie neuronal development and synaptic plasticity. Earlier we demonstrated that the voltage‐gated sodium channel (VGSC) activators, brevetoxin and antillatoxin, increased [Na+]i, stimulated Ca2+ influx through NMDARs and enhanced NMDAR‐mediated neurite outgrowth (Joju et al., 2009, Jabba et al., 2010). Here we tested whether VGSC activator‐induced neurite outgrowth may involve NMDAR‐dependent activation of the PI3K‐Akt pathway. Veratridine (VRT), a VGSC activator, was used in this study. VRT enhanced neurite outgrowth and dendritic arborization in immature cerebrocortical neurons and displayed a biphasic concentration‐response curve. VRT produced an elevation of [Na+]i and [Ca2+]i in a tetrodotoxin‐sensitive manner. Exposure to VRT increased Akt phosphorylation in immature cerebrocortical neurons. Either the NMDAR antagonist MK‐801, PI3K inhibitor LY294002 or calmodulin‐dependent protein kinase kinase (CaMKK) inhibitor STO‐609 abolished VRT‐induced Akt phosphorylation. VRT‐induced neurite outgrowth and dendritic arborization was abrogated by LY294002. These data suggest that VGSC activator‐enhanced neuritogenisis and dendritic arborization involves elevation of [Na+]i, and [Ca2+]i, and activation of the NMDAR‐PI3K‐Akt pathway.(NIH RO1 NS053398‐06)