title: 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: Division of Oral Physiology, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Sendai 980-8575, Japan. tkudo@m.tohoku.ac.jp
authors: Tada-aki
authors: TA
authors: Kudo
authors: Hiroyasu
authors: H
authors: Kanetaka
authors: Kazutoshi
authors: K
authors: Mizuno
authors: Yasuhiro
authors: Y
authors: Ryu
authors: Yoshiyuki
authors: Y
authors: Miyamoto
authors: Shoko
authors: S
authors: Nunome
authors: Ye
authors: Y
authors: Zhang
authors: Mitsuhiro
authors: M
authors: Kano
authors: Yoshinaka
authors: Y
authors: Shimizu
authors: Haruhide
authors: H
authors: Hayashi
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors; D002070:Butadienes / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System; D016501:Neurites / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D016716:PC12 Cells; D011494:Protein Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D019485:Bone Morphogenetic Proteins; D002070:Butadienes; D007546:Isoquinolines; C554430:LDN 193189; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; C113580:U 0126; C516138:dorsomorphin; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D020930:MAP Kinase Kinase Kinases; C041311:tropomyosin kinase; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide