CaMKII-Mediated CREB Phosphorylation Is Involved in Ca2+-Induced BDNF mRNA Transcription and Neurite Outgrowth Promoted by Electrical Stimulation.
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.
Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.|Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
Xiaodong
X
Yan
Department of Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an 710032, China.
Juanfang
J
Liu
Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Zhengxu
Z
Ye
Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Jinghui
J
Huang
Department of Hereditary and Development, Basic Unit, Fourth Military Medical University, Xi'an 710032, China.
Fei
F
He
Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Wei
W
Xiao
Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Xueyu
X
Hu
Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
Zhuojing
Z
Luo
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology*; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004558:Electric Stimulation; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008954:Models, Biological; D000071446:Neuronal Outgrowth / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D014158:Transcription, Genetic / Q000187:drug effects*
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D021122:Protein Subunits; D012333:RNA, Messenger; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium