Dorsomorphin stimulates neurite outgrowth in PC12 cells via activation of a protein kinase A-dependent MEK-ERK1/2 signaling pathway.

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.

• Authors: Tada-aki Kudo, Hiroyasu Kanetaka, Kazutoshi Mizuno, Yasuhiro Ryu, Yoshiyuki Miyamoto, Shoko Nunome, Ye Zhang, Mitsuhiro Kano, Yoshinaka Shimizu, Haruhide Hayashi
• Journal: Genes to cells : devoted to molecular & cellular mechanisms (Genes Cells) Vol. 16 Issue 11 Pg. 1121-32 (Nov 2011) ISSN: 1365-2443 [Electronic] England
• PMID: 21988724 (Publication Type: Journal Article)
• Copyright: © 2011 The Authors. Journal compilation © 2011 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.

Chemical References

• Bone Morphogenetic Proteins
• Butadienes
• Isoquinolines
• LDN 193189
• Nitriles
• Pyrazoles
• Pyrimidines
• Sulfonamides
• U 0126
• dorsomorphin
• Protein Kinases
• Cyclic AMP-Dependent Protein Kinases
• MAP Kinase Kinase Kinases
• tropomyosin kinase
• N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide

Topics

• Animals
• Bone Morphogenetic Proteins (antagonists & inhibitors)
• Butadienes (pharmacology)
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Gene Expression Regulation, Developmental (drug effects)
• Isoquinolines (pharmacology)
• MAP Kinase Kinase Kinases (antagonists & inhibitors, metabolism)
• MAP Kinase Signaling System
• Neurites (drug effects, enzymology, physiology)
• Nitriles (pharmacology)
• PC12 Cells
• Protein Kinases (metabolism)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Rats
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• Transcriptional Activation (drug effects)