We previously reported that tetrahydrobiopterin (6R-BH4), a natural cofacto
r for aromatic amino acid hydroxylases and nitric oxide synthase, stimulate
s dopamine release from rat striatum independently of its cofactor activity
. In the present study, we further investigated the effect of 6R-BH4 on dop
amine release using differentiated PC12 cells. In PC12 cells, GR-BH4 (10 mu
M and 30 mu M) stimulated dopamine release in a dose-related manner, which
was persisted in the presence of alpha-methyl-p-tyrosine (1 mM) or L-nitro
-arginine methyl ester (100 mu M). Dopamine release from PC12 cells was not
stimulated by 6S-BH4, a diastereoisomer of 6R-BH4, or sepiapterin, a precu
rsor of 6R-BH4. These results were consistent with the effects of 6R-BH4 on
dopamine release from rat striatum. Dopamine release induced by 6R-BH4 was
inhibited by nicardipine (1 mu M), suggesting that 6R-BH4-induced dopamine
release is mediated by Ca2+ channel activation. Ca-45(2+) uptake and intra
cellular Ca2+ concentration in PC12 cells were increased by 6R-BH4. Membran
e potential of PC12 cells was depolarized by 6R-BH4. These data taken toget
her suggest that 6R-BH4 stimulates dopamine release from PC12 cells by indu
cing membrane depolarization which is a trigger for Ca2+ channel activation
.