Abstract
Electrical stimulation (ES)-triggered up-regulation of brain-derived neurotrophic factor (BDNF) and neurite outgrowth in cultured rat postnatal dorsal root ganglion neurons (DRGNs) is calcium (Ca2+)-dependent. The effects of increased Ca2+ on BDNF up-regulation and neurite outgrowth remain unclear. We showed here that ES increased phosphorylation of the cAMP-response element binding protein (CREB). Blockade of Ca2+ suppressed CREB phosphorylation and neurite outgrowth. Down-regulation of phosphorylated (p)-CREB reduced BDNF transcription and neurite outgrowth triggered by ES. Furthermore, blockade of calmodulin-dependent protein kinase II (CaMKII) using the inhibitors KN93 or KN62 reduced p-CREB, and specific knockdown of the CaMKIIα or CaMKIIβ subunit was sufficient to suppress p-CREB. Recombinant BDNF or hyperforin reversed the effects of Ca2+ blockade and CaMKII knockdown. Taken together, these data establish a potential signaling pathway of Ca2+-CaMKII-CREB in neuronal activation. To our knowledge, this is the first report of the mechanisms of Ca2+-dependent BDNF transcription and neurite outgrowth triggered by ES. These findings might help further investigation of complex molecular signaling networks in ES-triggered nerve regeneration in vivo.
Highlights
Electrical stimulation (ES) induces regeneration-related gene expression and neurite outgrowth of dorsal root ganglion neurons (DRGNs) [1, 2], and accelerates axon regeneration of central and peripheral nerves [3, 4]
ES induced neurite outgrowth in the ES+/CaMKIIα shRNA or CaMKIIβ group compared to the ES-/CaMKIIα shRNA or ES-/CaMKIIβ shRNA group, separately (P < 0.05) (Fig 7B). These results suggest that CaMKIIα and CaMKIIβ are both required for ES-induced neurite outgrowth in DRGNs
It has been established that ES induces brain-derived neurotrophic factor (BDNF) transcription and neurite outgrowth accompanied by an elevation of intracellular Ca2+ in rat DRGNs [5]
Summary
Electrical stimulation (ES) induces regeneration-related gene expression and neurite outgrowth of dorsal root ganglion neurons (DRGNs) [1, 2], and accelerates axon regeneration of central and peripheral nerves [3, 4]. Our previous study showed that ES accelerates neurite outgrowth and expression of brain-derived neurotrophic factor (BDNF), accompanied by an elevation in PLOS ONE | DOI:10.1371/journal.pone.0162784. CaMKII/CREB Mediates ES-Induced Neurite Outgrowth intracellular calcium (Ca2+) [5]. BDNF, mediates neuronal development and synaptic function [6], which is critical for differentiation and survival of neurons during development [7]. BDNF transcription is Ca2+-dependent [6, 8]. The cAMP-response element binding protein (CREB) mediates BDNF transcription [6]. Studies have shown that Ca2+, as an important messenger acting via Ca2+/calmodulin-dependent protein kinases (CaMKs), triggers phosphorylation of CREB [13], and that phosphorylated CREB (pCREB) activates BDNF transcription by binding to a calcium response element within the gene [6]
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