Abstract
We previously showed that 20-O-β-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 β, Aβ(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.
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References
Bagutti C, Forro G, Ferralli J, Rubin B, Chiquet-Ehrismann R (2003). The intracellular domain of teneurin-2 has a nuclear function and represses zic-1-mediated transcription. J Cell Sci 116: 2957–2966.
Edström A, Ekström PA (2003). Role of phosphatidylinositol 3-kinase in neuronal survival and axonal outgrowth of adult mouse dorsal root ganglia explants. J Neurosci Res 74: 726–735.
Klesse LJ, Parada LF (1999). Trks: signal transduction and intracellular pathways. Microsc Res Tech 45: 210–216.
Lee SJ, Sung JH, Lee SJ, Moon CK, Lee BH (1999). Antitumor activity of a novel ginseng saponin metabolite in human pulmonary adenocarcinoma cells resistant to cisplatin. Cancer Lett 144: 39–43.
Levine A, Bashan-Ahrend A, Budai-Hadrian O, Gartenberg D, Menasherow S, Wides R (1994). Odd Oz: a novel Drosophila pair rule gene. Cell 77: 587–598.
Menager C, Arimura N, Fukata Y, Kaibuchi K (2004). PIP3 is involved in neuronal polarization and axon formation. J Neurochem 9: 109–118.
Minet AD, Chiquet-Ehrismann R (2000). Phylogenetic analysis of teneurin genes and comparison to the rearrangement hot spot elements of E. coli. Gene 257: 87–97.
Odani T, Tanizawa H, Takino Y (1983). Studies on the absorption, distribution, excretion and metabolism of ginseng saponins. III. The absorption, distribution and excretion of ginsenoside Rb1 in the rat. Chem Pharm Bull 31: 1059–1066.
Otaki JM, Firestein S (1999). Neurestin: putative transmembrane molecule implicated in neuronal development. Dev Biol 212: 165–181.
Rodgers EE, Theibert AB (2002). Functions of PI3-kinase in development of the nervous system. Int Dev Neurosci 20: 187–197.
Rubin BP, Tucker RP, Brown-Luedi M, Martin D, Chiquet-Ehrismann R (2002). Teneurin 2 is expressed by the neurons of the thalamofugal visual system in situ and promotes homophilic cell–cell adhesion in vitro. Development 129: 4697–4705.
Rubin BP, Tucker RP, Martin D, Chiquet-Ehrismann R (1999). Teneurins: a novel family of neuronal cell surface proteins in vertebrates, homologous to the Drosophila pair-rule gene product Ten-m. Dev Biol 216: 195–209.
Schwamborn JC, Püschel AW (2004). The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity. Nat Neurosci 7: 923–929.
Shi SH, Jan LY, Jan YN (2003). Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity. Cell 112: 63–75.
Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M (2003). Degeneration of ginsenosides in humans after oral administration. Drug Metab Dispos 31: 1065–1071.
Tohda C, Matsumoto N, Zou K, Meselhy MR, Komatsu K (2004). Aβ (25–35)-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by M1, A metabolite of protopanaxadiol-type saponins. Neuropsychopharmacology 29: 860–868.
Tohda C, Matsumoto N, Zou K, Meselhy RM, Komatsu K (2002). Axonal and dendritic extension by protopanaxadiol-type saponins from ginseng drugs in SK-N-SH cells. Jpn J Pharmacol 90: 254–262.
Tucker RP, Chiquet-Ehrismann R, Chevron MP, Martin D, Hall RJ, Rubin BP (2001). Teneurin-2 is expressed in tissues that regulate limb and somite pattern formation and is induced in vitro and in situ by FGF8. Dev Dyn 220: 27–39.
Wakabayashi C, Murakami K, Hasegawa H, Murata J, Saiki I (1998). An intestinal bacterial metabolite of ginseng protopanaxadiol saponins has the ability to induce apoptosis in tumor cells. Biochem Biophys Res Commun 246: 725–730.
Acknowledgements
We thank Dr Zou Kun for identifying the structure of M1. This work was supported by the Uehara Memorial Foundation.
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Tohda, C., Hashimoto, I., Kuboyama, T. et al. Metabolite 1 of Protopanaxadiol-Type Saponins, an Axonal Regenerative Factor, Stimulates Teneurin-2 Linked by PI3-Kinase Cascade. Neuropsychopharmacol 31, 1158–1164 (2006). https://doi.org/10.1038/sj.npp.1300943
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DOI: https://doi.org/10.1038/sj.npp.1300943
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