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We previously reported that tetrahydrobiopterin (6R-BH4), a natural cofactor for aromatic amino acid hydroxylases and nitric oxide synthase, stimulates dopamine release from rat striatum independently of its cofactor activity. In the present study, we further investigated the effect of 6R-BH4 on dopamine release using differentiated PCl2 cells. In PCl2 cells, 6R-BH4 (l0 ,uM and 30 ;¢M) stimulated dopamine release in a dose-related manner, which was persisted in the presence of a'—methyl-p-tyrosine (l mM) or L-nitro-arginine methyl ester (100 ;¢M). Dopamine release from PCl2 cells was not stimulated by 6S-BH4, a diastereoisomer of 6R-BH4, or sepiapterin, a precursor 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 (l ;,¢M), suggesting that 6R-BH4-induced dopamine release is mediated by Ca2+ channel activation. ‘*5Ca2+ uptake and intracellular Ca2+ concentration in PCl2 cells were increased by 6R-BH4. Membrane potential of PCl2 cells was depolarized by 6R-BH4. These data taken together suggest that 6R-BH4 stimulates dopamine release from PCl2 cells by inducing membrane depolarization which is a trigger for Ca2+ channel activation. Tetrahydrobiopterin (6R-BH4) is a natural cofactor for phenylalanine hydroxylase (1), tyrosine hydroxylase (ll), tryptophan hydroxylase (9) and nitric oxide synthase (7). We previously reported that 6R-BH4 stimulates dopamine release from rat striatum (2-4). The dopamine releasing action of 6R-BH4 was independent of its cofactor activity (2, 3). That is, 6R-BH4 stimulated dopamine release under inhibition of tyrosine hydroxylase or nitric oxide synthase. In dorsal motor nucleus of vagus of rats, 6R-BI—I4 activated Ca2+ channels (12). These results suggest that 6R-BH4 stimulated dopamine release by activating Ca” channels. We previously reported that Correspondence and reprint requests to: Dr K. Koshimura Tel: +81-853-20-2184 Fax: +81-853-23-8650 e-mail: kunio@shimane-med.ac.jp 6R-BH4 increased “Ca” uptake (5) and intracellular Ca” concentration in differentiated PCl2 cells (6). These data suggest that 6R-BI-I4 activates Ca” channels in differentiated PCl2 cells. In the present study, to further investigate the dopamine releasing action of 6R-BH4, we examined the effect of 6R-BI—I4 on dopamine release from differentiated PCl2 cells. We demonstrated that 6R-BH4 activates Ca2+ channels by inducing membrane depolarization in differentiated PCl2 cells. MATERIALS AND METHODS

Effect of Tetrahydrobiopterin on Dopamine Release from PC12 Cells