title: Increase in secretion of glial cell line-derived neurotrophic factor from glial cell lines by inhibitors of vacuolar ATPase.
abstract: Glial cell line-derived neurotrophic factor (GDNF) was reported to be effective for treating subjects with neurodegenerative diseases such as Parkinson's disease. In search of finding a compound which promotes GDNF secretion, we found that concanamycin A (ConA), a vacuolar ATPase (V-type ATPase) inhibitor purified from Streptomyces diastatochromogens, enhanced GDNF secretion from glioma cells. The rat glioma cell line, C6, and the human glioma cell lines, U87MG and T98G, abundantly expressed GDNF mRNA, and secreted GDNF into culture media, and this event was potently enhanced by a Ca(2+) ionophore and by phorbol ester, as noted in other cells. ConA concentration dependently and potently increased GDNF release from C6, U87MG and T98G cells into culture media. In addition, ConA enhanced GDNF secretion from astrocyte primary cultures prepared from the human fetus with the same potency seen in glioma cell lines. Likewise, another V-type ATPase inhibitor, bafilomycinA1 facilitated GDNF release from C6, U87MG and T98G glioma cells, in a concentration-dependent manner. The potencies of these V-type ATPase inhibitors in enhancing GDNF secretion were consistent with those which inhibited V-type ATPase activity. These results suggest that blockade of V-type ATPase potently stimulates the secretion of GDNF from glial cells. The V-type ATPase inhibitors may be beneficial to use for the treatment of diseases in which increase in GDNF could be effective.
authors.affiliation: Medicinal Pharmacology Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Saitama, Saitama 330-8530, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Nishiguchi
authors.forename: Kimiko
authors.initials: K
authors.lastname: Tokugawa
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Akama
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Nozawa
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ueki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kameo
authors.forename: Shigeru
authors.initials: S
authors.lastname: Okuyama
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001483:Base Sequence; D000001:Calcimycin / Q000494:pharmacology; D003208:Concanavalin A / Q000494:pharmacology; D017077:Culture Media, Conditioned; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D018942:Macrolides; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
chemical_list: D000900:Anti-Bacterial Agents; D017077:Culture Media, Conditioned; D017931:DNA Primers; D004791:Enzyme Inhibitors; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018942:Macrolides; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D003208:Concanavalin A; D000001:Calcimycin; C040929:bafilomycin A1; D025262:Vacuolar Proton-Translocating ATPases