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 a nd play an important role in hepatobiliary excretion. We investigated the t ransport function and subcellular localization of mrp6, a novel member of t he mrp family, in rat liver. Transport studies in vesicles isolated from mr p6 expressing Sf9 cells identified the anionic cyclopentapeptide and endoth elin receptor antagonist BQ-123 as a substrate of mrp6 (K-m similar to 17 m u M). Besides BQ-123, which is also a substrate of mrp2 (K-m similar to 124 mu M), no other common substrates were found for mrp2, mrp6, and the canal icular bile salt export pump Bsep. The cyclic peptides endothelin I and Arg (8)-vasopressin were transported by mrp2 but not by mrp6. Using a polyclona l antiserum raised against a C-terminal peptide, mrp6 was found to be local ized at the lateral and, to a lesser extent, at the canalicular plasma memb rane of hepatocytes. The limited overlap of the substrate specificity with the canalicular export pumps mrp2 and Bsep indicates that mrp6 does not pla y a major role in canalicular organic anion excretion. However, its dual lo calization at the lateral and canalicular plasma membrane suggests that mrp 6 might fulfill a "housekeeping" transport function involved in the regulat ion of paracellular and/or transcellular solute movement from blood into bi le.