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Dopamine‐Releasing Action of 6 R ‐ l ‐ erythro ‐Tetrahydrobiopterin: Analysis of Its Action Site Using Sepiapterin
Author(s) -
Koshimura Kunio,
Miwa Soichi,
Watanabe Yasuyoshi
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.63020649.x
Subject(s) - tetrahydrobiopterin , biopterin , tyrosine hydroxylase , tyrosine , extracellular , dopamine , tyrosine 3 monooxygenase , microdialysis , chemistry , monoamine neurotransmitter , nitric oxide synthase , nitric oxide , medicine , gtp cyclohydrolase i , endocrinology , catecholamine , biochemistry , biology , serotonin , receptor
Recently, we reported that 6 R ‐ l ‐ erythro ‐tetrahydrobiopterin (6 R ‐BH 4 ), a natural cofactor for hydroxylases of tyrosine and tryptophan, has a monoamine‐releasing action independent of its cofactor activity. Here we attempted to determine whether 6 R ‐BH 4 acts inside the cell or from the outside of the cell by using brain microdialysis in the rat striatum. For this purpose, sepiapterin, an immediate precursor of 6 R ‐BH 4 in the salvage pathway, was used to selectively increase the intracellular 6 R ‐BH 4 levels. Dialytic perfusion of sepiapterin increased tissue levels of reduced biopterin (mainly 6 R ‐BH 4 ) but not the extracellular levels. Administration of sepiapterin increased the extracellular levels of 3,4‐dihydroxyphenylalanine (DOPA) (an index of in vivo tyrosine hydroxylase activity) and of dopamine (DA) (an index of in vivo DA release). Either of the increases was eliminated after pretreatment with a tyrosine hydroxylase inhibitor α‐methyl‐ p ‐tyrosine. Administration of 6 R ‐BH 4 increased extracellular levels of reduced biopterin, DOPA, and DA. After pretreatment with α‐methyl‐ p ‐tyrosine, the increase in DOPA levels was abolished, but most of the increase in DA levels persisted. The increase in DA levels also persisted after pretreatment with nitric oxide synthase inhibitors. These data demonstrate that 6 R ‐BH 4 stimulates DA release directly, independent of its cofactor action for tyrosine hydroxylase and nitric oxide synthase, by acting from the outside of neurons.