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.