Abstract
Incubation of PC 12 cells with the sulfonylurea drug, glipizide (1-100 microM), increased intracellular levels of the acidic metabolites of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The levels of these acids in the medium were decreased, indicating the presence of a sulfonylurea-sensitive organic anion transporter. In the present study, we demonstrate that the sulfonylurea-sensitive transport of acidic dopamine metabolites is unidirectional, ATP dependent, unaffected by ouabain or by tetrodotoxin and blocked by drugs that interact with the multidrug-resistance protein-1 (MRP1). However, over-expression of MRP1 did not affect transport of the acid metabolites. The pharmacological profile and ion dependence of the transporter also differs from that of known ATP-binding cassette (ABC) family members. Using microdialysis, we also demonstrated a sulfonylurea-sensitive transport process in the striatum of freely moving rats. These results show that acidic dopamine metabolites are actively secreted from dopaminergic cells into surrounding extracellular fluid by a previously undescribed transporter.
MeSH terms
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3,4-Dihydroxyphenylacetic Acid / metabolism*
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3T3 Cells
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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ATP-Binding Cassette Transporters / drug effects
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Biological Transport, Active
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Dopamine / metabolism*
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Glipizide / pharmacology*
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Glyburide / metabolism
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Homovanillic Acid / metabolism*
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Male
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Mice
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Microdialysis
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Multidrug Resistance-Associated Proteins
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PC12 Cells
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Potassium Channels / genetics
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Potassium Channels / metabolism
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Potassium Channels, Inwardly Rectifying
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Probenecid / pharmacology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, Drug
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Rhodamines / metabolism
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Sulfonylurea Receptors
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Transfection
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP-Binding Cassette Transporters
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Multidrug Resistance-Associated Proteins
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Potassium Channels
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Potassium Channels, Inwardly Rectifying
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RNA, Messenger
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Receptors, Drug
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Rhodamines
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Sulfonylurea Receptors
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3,4-Dihydroxyphenylacetic Acid
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Probenecid
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Glyburide
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Dopamine
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Homovanillic Acid
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Glipizide