Metabolite 1 of protopanaxadiol-type saponins, an axonal regenerative factor, stimulates teneurin-2 linked by PI3-kinase cascade.
We previously showed that 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (M1), a metabolite of protopanaxadiol-type ginseng saponins by intestinal bacteria had axonal extension activity in degenerated neurons, and improved memory disorder and synaptic loss induced by an active fragment of amyloid beta, Abeta(25-35). It is unknown how M1 shows these effects in neurons. To clarify the signal transduction mechanism of M1-induced axonal extension, phosphorylated proteins by M1 stimulation were identified because most cellular signal pathways are regulated by phosphorylation/dephosphorylation. The combination of immunoprecipitation and MALDI-TOF-MS revealed that teneurin-2 and mPar3 were specifically phosphorylated by M1 stimulation. Because mPar3 is known as an axonal specifying molecule and to be regulated by phosphatidylinositol 3-kinase (PI3-kinase), the involvement of teneurin-2 and PI3-kinase in the M1 signal was studied. In teneurin-2-deficient cortical neurons, M1-induced axonal extension and PI3-kinase activation were significantly inhibited. In addition, treatment with PI3-kinase inhibitor also reduced M1-induced axonal extension. These results suggest that M1 induces axonal outgrowth through the teneurin-2-PI3-kinase cascade.
Tohda
Chihiro
C
Division of Biofunctional Evaluation, Research Center for Ethnomedicine, Institute of Natural Medicine, University of Toyama, Sugitani, Toyama, Japan. chihiro@ms.toyama-mpu.ac.jp
Hashimoto
Itsuki
I
Kuboyama
Tomoharu
T
Komatsu
Katsuko
K
D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D008565:Membrane Proteins / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D010455:Peptides / Q000633:toxicity; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012502:Sapogenins / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D014162:Transfection / Q000379:methods; D014315:Triterpenes / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D002867:Chromones; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D012502:Sapogenins; D014315:Triterpenes; C489787:MAP2 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C062916:protopanaxadiol