Acidic dopamine metabolites are actively extruded from PC12 cells by a novel sulfonylurea-sensitive transporter.
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.
Lamensdorf
I
I
Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1620, USA. lamensdo@helix.nih.gov
Hrycyna
C
C
He
L P
LP
Nechushtan
A
A
Tjurmina
O
O
Harvey-White
J
J
Eisenhofer
G
G
Rojas
E
E
Kopin
I J
IJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism*; D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D004298:Dopamine / Q000378:metabolism*; D005913:Glipizide / Q000494:pharmacology*; D005905:Glyburide / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D017551:Microdialysis; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016716:PC12 Cells; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D011339:Probenecid / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug; D012235:Rhodamines / Q000378:metabolism; D064233:Sulfonylurea Receptors; D014162:Transfection
D015102:3,4-Dihydroxyphenylacetic Acid; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D004298:Dopamine; D005913:Glipizide; D005905:Glyburide; D006719:Homovanillic Acid; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011339:Probenecid; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D011955:Receptors, Drug; D012235:Rhodamines; D064233:Sulfonylurea Receptors