| Increased expression of the 190 kDa membrane transporter multidrug resistance protein 1 (MRP1) is associated with drug resistance in many cancers and is a serious impediment to successful chemotherapy. In the present study, eight charged amino acids in and around the transmembrane (TM) segments of MSD3 of MRP1 were mutated to the opposite charge and the effects on MRP1 protein expression levels and transport of five organic anion substrates were examined. Transport could only be achieved with like charge substitutions of Asp 1084 and Glu1204, suggesting that the residue charge was important for MRP1 function at positions 1204 and 1084. Lys substituted Arg1197 and Arg1249 MRP1 mutants remained inactive, indicating that both charge and size of the amino acid side chain were important at the 1197 and 1249 positions. We conclude that charged residues in MSD3 can play a role in both the expression and transport function of MRP1. (Abstract shortened by UMI.)... |
