Cyclic GMP-dependent neurite outgrowth by genipin and nerve growth factor in PC12h cells.
We have demonstrated previously that a natural iridoid compound, genipin, induced neuritogenesis through activation of nitric oxide synthase (NOS) and mitogen-activated protein kinase (MAPK) in PC12h cells. In this paper, we investigated whether cyclic GMP (cGMP) and cGMP-dependent protein kinase (PKG) are involved in the neuritogenesis as a result of NOS activation. Furthermore, we also investigated the relationship between cGMP and MAPK activation in the signaling pathway. The genipin-induced neuritogenesis accompanied by induction of neurofilament was significantly inhibited by 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) and KT5823, inhibitors of soluble guanylate cyclase and PKG, respectively. Genipin-induced MAPK phosphorylation was also abolished by ODQ. These inhibitory effects of ODQ were similar to those observed for nerve growth factor (NGF)-induced neurite outgrowth and MAPK phosphorylation. The membrane-permeable cGMP analog, 8-Bromo-cGMP, had prominent neuritogenic activity, which was completely inhibited by a MAPK kinase inhibitor, PD98059. These results suggest that the soluble guanylate cyclase-PKG signaling pathway is important for MAPK activation by genipin as well as NGF during neuritogenesis in PC12h cells.
Yamazaki
Matsumi
M
Department of Biodynamics, Faculty of Pharmaceutical Sciences, Hokuriku University, HO-3 Kanagawa-machi, Kanazawa, Ishikawa 920-1181, Japan. m-yamazaki@hokuriku-u.ac.jp
Chiba
Kenzo
K
Mohri
Tetsuro
T
Hatanaka
Hiroshi
H
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D006152:Cyclic GMP / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D004591:Electrophoresis, Polyacrylamide Gel; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D057889:Iridoid Glycosides; D039823:Iridoids; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites / Q000502:physiology*; D016900:Neurofilament Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D016716:PC12 Cells; D010766:Phosphorylation; D011714:Pyrans / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D057889:Iridoid Glycosides; D039823:Iridoids; D009414:Nerve Growth Factors; D016900:Neurofilament Proteins; D011714:Pyrans; D009569:Nitric Oxide; C007834:genipin; D017869:Cyclic GMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP