BDNF activates CaMKIV and PKA in parallel to block MAG-mediated inhibition of neurite outgrowth.
The environment of the adult CNS prevents axonal regeneration after injury. This inhibition of axonal regeneration can be blocked by elevating cAMP. Previously, we showed that the cAMP pathway can be activated via pre-treatment with neurotrophins and requires activation of several signaling pathways which converge at activation of the transcription factor, CREB. Here, we show that calcium/calmodulin-dependent kinase IV (CaMKIV) is necessary for the neurotrophin-induced phosphorylation of CREB and the block of myelin-mediated inhibition of axonal growth. Pharmacological inhibition of CaMKIV or over-expression of a dominant-negative mutant form of CaMKIV blocks the neurotrophin effect. Interestingly, CaMKIV activation is not necessary if cAMP levels is already elevated. Finally, calcium flux from intracellular stores is necessary for this CaMKIV signaling. These results demonstrate that CaMKIV is another player in the neurotrophin-induced signaling which leads to axonal regeneration and therefore, is a potential target for therapeutic intervention following injury to the adult CNS.
Spencer
Timothy K
TK
Department of Biological Sciences, Hunter College, City University of New York, New York, New York 10065, USA. ts2319@columbia.edu
Mellado
Wilfredo
W
Filbin
Marie T
MT
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D016466:CHO Cells; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D006224:Cricetinae; D003412:Cricetulus; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D006131:Growth Inhibitors / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018992:Myelin-Associated Glycoprotein / Q000037:antagonists & inhibitors* / Q000502:physiology*; D009433:Neural Inhibition / Q000502:physiology*; D009434:Neural Pathways / Q000502:physiology; D016501:Neurites / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats
D019208:Brain-Derived Neurotrophic Factor; D006131:Growth Inhibitors; D018992:Myelin-Associated Glycoprotein; D017868:Cyclic AMP-Dependent Protein Kinases; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse