Transport function and hepatocellular localization of mrp6 in rat liver.
The multidrug resistance-associated proteins (Mrps) constitute a family of cellular export pumps of the ATP-binding cassette transporter superfamily and play an important role in hepatobiliary excretion. We investigated the transport function and subcellular localization of mrp6, a novel member of the mrp family, in rat liver. Transport studies in vesicles isolated from mrp6 expressing Sf9 cells identified the anionic cyclopentapeptide and endothelin receptor antagonist BQ-123 as a substrate of mrp6 (K(m) approximately 17 microM). Besides BQ-123, which is also a substrate of mrp2 (K(m) approximately 124 microM), no other common substrates were found for mrp2, mrp6, and the canalicular bile salt export pump Bsep. The cyclic peptides endothelin I and Arg(8)-vasopressin were transported by mrp2 but not by mrp6. Using a polyclonal antiserum raised against a C-terminal peptide, mrp6 was found to be localized at the lateral and, to a lesser extent, at the canalicular plasma membrane of hepatocytes. The limited overlap of the substrate specificity with the canalicular export pumps mrp2 and Bsep indicates that mrp6 does not play a major role in canalicular organic anion excretion. However, its dual localization at the lateral and canalicular plasma membrane suggests that mrp6 might fulfill a "housekeeping" transport function involved in the regulation of paracellular and/or transcellular solute movement from blood into bile.
Madon
J
J
Division of Clinical Pharmacology, Department of Medicine, University Hospital, Zurich, Switzerland.
Hagenbuch
B
B
Landmann
L
L
Meier
P J
PJ
Stieger
B
B
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism; D001483:Base Sequence; D001692:Biological Transport / Q000502:physiology; D016466:CHO Cells; D019556:COS Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D006367:HeLa Cells; D006801:Humans; D007313:Insecta; D008099:Liver / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010456:Peptides, Cyclic / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions; D014018:Tissue Distribution; D014158:Transcription, Genetic
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D000959:Antihypertensive Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010456:Peptides, Cyclic; D012333:RNA, Messenger; C072247:cyclo(Trp-Asp-Pro-Val-Leu)