RRC ID 69832
Author Kudo TA, Kanetaka H, Mizuno K, Ryu Y, Miyamoto Y, Nunome S, Zhang Y, Kano M, Shimizu Y, Hayashi H.
Title Dorsomorphin stimulates neurite outgrowth in PC12 cells via activation of a protein kinase A-dependent MEK-ERK1/2 signaling pathway.
Journal Genes Cells
Abstract In this study, we investigated the effect of dorsomorphin, a selective inhibitor of bone morphogenetic protein (BMP) signaling, on rat PC12 pheochromocytoma cell differentiation. PC12 cells can be induced to differentiate into neuron-like cells possessing elongated neurites by nerve growth factor, BMP2, and other inducers. Cells were incubated with BMP2 and/or dorsomorphin, and the extent of neurite outgrowth was evaluated. Unexpectedly, BMP2-mediated neuritogenesis was not inhibited by co-treatment with dorsomorphin. We also found that treatment with dorsomorphin alone, but not another BMP signaling inhibitor, LDN-193189, induced neurite outgrowth in PC12 cells. To further understand the mechanism of action of dorsomorphin, the effects of this drug on intracellular signaling were investigated using the following signaling inhibitors: the ERK kinase (MEK) inhibitor U0126; the tropomyosin-related kinase A inhibitor GW441756; and the protein kinase A (PKA) inhibitor H89. Dorsomorphin induced rapid and sustained ERK1/2 activation; however, dorsomorphin-mediated ERK1/2 activation and neuritogenesis were robustly inhibited in the presence of U0126 or H89, but not GW441756. These findings suggest that dorsomorphin has the potential to induce neuritogenesis in PC12 cells, a response that requires the activation of PKA-dependent MEK-ERK1/2 signaling.
Volume 16(11)
Pages 1121-32
Published 2011-11-1
DOI 10.1111/j.1365-2443.2011.01556.x
PMID 21988724
MeSH Animals Bone Morphogenetic Proteins / antagonists & inhibitors Butadienes / pharmacology Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors Cyclic AMP-Dependent Protein Kinases / metabolism* Dose-Response Relationship, Drug Gene Expression Regulation, Developmental / drug effects Isoquinolines / pharmacology MAP Kinase Kinase Kinases / antagonists & inhibitors MAP Kinase Kinase Kinases / metabolism MAP Kinase Signaling System* Neurites / drug effects* Neurites / enzymology Neurites / physiology* Nitriles / pharmacology PC12 Cells Protein Kinases / metabolism Pyrazoles / pharmacology* Pyrimidines / pharmacology* Rats Signal Transduction / drug effects Sulfonamides / pharmacology Transcriptional Activation / drug effects
IF 1.655
Human and Animal Cells PC-12(RCB0009)