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Sodium channel activator‐induced neuronal development is NMDA receptor dependent and involves a Ca 2+ /calmodulin kinase (CaMK)‐CREB‐BDNF signaling pathway
Author(s) -
George Joju,
Murray Thomas F
Publication year - 2010
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.24.1_supplement.770.11
Subject(s) - creb , microbiology and biotechnology , nmda receptor , camk , chemistry , brain derived neurotrophic factor , neurotrophic factors , phosphorylation , activator (genetics) , transcription factor , neuroscience , biology , protein kinase a , receptor , autophosphorylation , biochemistry , gene
Many aspects of activity‐dependent neuronal development such as dendritic arborization, spinogenesis and synaptogenesis are mediated through NMDA receptor [NMDAR]‐dependent Ca 2+ signaling mechanisms. Brevetoxin‐2 (PbTx‐2), an activator of voltage‐gated sodium channels, mimics activity‐dependent control of neuronal development by elevating intracellular sodium levels and augmenting NMDAR function. PbTx‐2 enhanced cerebrocortical neuron spinogenesis and synapse density. Morphological analysis showed that PbTx‐2 enhanced spinogenesis by stimulating dendritic filopodia formation. Pharmacological evaluation showed that the PbTx‐2 induced neuronal plasticity was mediated by signaling mechanisms downstream of CaMKK. PbTx‐2 exposure produced phosphorylation and activation of CaMKI (Thr177) and CaMKII (Thr286). PbTx‐2 also induced ErK 1/2, but not Akt, phosphorylation. CREB is known to be an activity‐regulated transcription factor, and PbTx‐2 exposure increased CREB phosphorylation at Ser‐133. Assessment of brain derived neurotrophic factor (BDNF) transcription with RT‐PCR demonstrated that BDNF mRNA expression level increased in a time and PbTx‐2 concentration dependent manner. These findings suggest that the sodium channel activator influence on neuronal developmental involves NMDAR‐mediated CaMK signaling with downstream activation of CREB‐dependent transcription of BDNF.