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Sodium channel activator‐induced neurite outgrowth is NMDA receptor dependent and involves a TrkB‐PLCγ‐PI3K‐Akt pathway
Author(s) -
Jabba Sairam V,
Murray Thomas F
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1003.3
Subject(s) - tropomyosin receptor kinase b , microbiology and biotechnology , pi3k/akt/mtor pathway , ly294002 , protein kinase b , chemistry , activator (genetics) , mapk/erk pathway , trk receptor , nmda receptor , signal transduction , neurite , neurotrophin , receptor , neurotrophic factors , biology , biochemistry , in vitro
Calcium influx through N‐methyl D‐aspartate receptors (NMDAR) regulates signaling cascades that underlie activity‐dependent neuronal development, including the expression and release of BDNF with activation of TrkB pathway. BDNF‐TrkB mediated neuronal development primarily involves three pathways: the PI3K, MAPK and PLCγ systems. Voltage‐gated sodium channel (VGSC) activators promote neuronal development by increasing [Na + ] i and upregulating NMDAR function. We examined the effect of the sodium channel activator veratridine (VRT) on neurite outgrowth (NOG) and BDNF‐TrkB signaling in DIV1 cerebrocortical neurons. VRT enhanced NOG and this response was dependent on NMDARs and TrkB signaling. Inhibitors of NMDAR (MK‐801), TrkB (K‐252a), PI3K (LY294002), and PLCγ (U73122) inhibited VRT‐enhanced NOG. VRT increased [Na + ] I and [Ca 2+ ] i . VRT‐induced elevation of Ca 2+ involved VGSCs, NMDARs and PLCγ sensitive intracellular Ca 2+ stores. VRT stimulated phosphorylation of TrkB (Y816: activates PLCγ) and Akt, a downstream effector of the BDNF‐TrkB‐PI3K pathway. VRT‐induced Akt phosphorylation involved VGSC‐NMDAR‐CaMKK‐PI3K signaling. VRT also activated ERK1/2 and CREB: downstream effectors of the MAPK pathway. These data suggest that VRT‐enhanced NOG involves elevation of [Na + ] i, and activation of NMDAR‐BDNF‐TrkB signaling with subsequent engagement of downstream PLCγ, PI3K and MAPK pathways. NIH RO1 NS053398 ‐06