title: Structure-Activity Relationship Study of the Neuritogenic Potential of the Glycan of Starfish Ganglioside LLG-3 (‡).
abstract: LLG-3 is a ganglioside isolated from the starfish Linchia laevigata. To clarify the structure-activity relationship of the glycan of LLG-3 toward rat pheochromocytoma PC12 cells in the presence of nerve growth factor, a series of mono- to tetrasaccharide glycan derivatives were chemically synthesized and evaluated in vitro. The methyl group at C8 of the terminal sialic acid residue was crucial for neuritogenic activity, and the terminal trisaccharide moiety was the minimum active motif. Furthermore, the trisaccharide also stimulated neuritogenesis in human neuroblastoma SH-SY5Y cells via mitogen-activated protein kinase (MAPK) signaling. Phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was rapidly induced by adding 1 or 10 nM of the trisaccharide. The ratio of phosphorylated ERK to ERK reached a maximum 5 min after stimulation, and then decreased gradually. However, the trisaccharide did not induce significant Akt phosphorylation. These effects were abolished by pretreatment with the MAPK inhibitor U0126, which inhibits enzymes MEK1 and MEK2. In addition, U0126 inhibited the phosphorylation of ERK 1/2 in response to the trisaccharide dose-dependently. Therefore, we concluded that the trisaccharide promotes neurite extension in SH-SY5Y cells via MAPK/ERK signaling, not Akt signaling.
authors.affiliation: Department of Applied Bioorganic Chemistry, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. glyco_gf@gifu-u.ac.jp.
authors.forename: Megumi
authors.initials: M
authors.lastname: Yamagishi
authors.affiliation: Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan. ritsuko@gifu-u.ac.jp.|Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. ritsuko@gifu-u.ac.jp.
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Hosoda-Yabe
authors.affiliation: Department of Applied Bioorganic Chemistry, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. ritsuko@gifu-u.ac.jp.|Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan. ritsuko@gifu-u.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Tamai
authors.affiliation: Department of Applied Bioorganic Chemistry, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. ritsuko@gifu-u.ac.jp.|Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan. ritsuko@gifu-u.ac.jp.
authors.forename: Miku
authors.initials: M
authors.lastname: Konishi
authors.affiliation: Department of Applied Bioorganic Chemistry, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. aimamura@gifu-u.ac.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Imamura
authors.affiliation: Department of Applied Bioorganic Chemistry, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. ishida@gifu-u.ac.jp.
authors.forename: Hideharu
authors.initials: H
authors.lastname: Ishida
authors.affiliation: Department of Applied Life Science, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. yabet@gifu-u.ac.jp.
authors.forename: Tomio
authors.initials: T
authors.lastname: Yabe
authors.affiliation: Department of Applied Bioorganic Chemistry, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. hando@gifu-u.ac.jp.|Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan. hando@gifu-u.ac.jp.
authors.forename: Hiromune
authors.initials: H
authors.lastname: Ando
authors.affiliation: Department of Applied Bioorganic Chemistry, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. ritsuko@gifu-u.ac.jp.|Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Yoshida Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan. ritsuko@gifu-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kiso
mesh_terms: D000818:Animals; D002070:Butadienes / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005732:Gangliosides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011134:Polysaccharides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013215:Starfish / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002070:Butadienes; D005732:Gangliosides; D009570:Nitriles; D011134:Polysaccharides; C113580:U 0126; D020932:Nerve Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: MAPK/ERK signaling; PC12 cell; SH-SY5Y cell; ganglioside; neurite outgrowth; starfish; structure-activity relationship