Download (4Mb) - Etheses - Saurashtra University

Part-IIIAdvances Dihydropyridines and …MRPs belong to the ABCC-subfamily, comprising eleven members in the humangenome. Most of these proteins (ABCC1-6) have been identified as active, ATPdependentmembrane transporters for various anticancer agents and organic anions. 12-14,17In contrast to these active transporters, the cystic fibrosis transmembrane conductanceregulator, ABCC7 (CFTR) is a regulated chloride channel, while ABCC8 (SUR1) andABCC9 (SUR2) are called sulfonylurea receptors and best described as intracellular ATPsensors, regulating the permeability of specific K + channels. Nothing is currently knownabout the function of ABCC10 and ABCC11. 11,13,27,28The predicted membrane topology of MRP1 is shown in Figure 2. According to currentnotion, in addition to an MDR1-like core, MRP1 contains an additional N-terminalsegment of about 280 amino acids. A major part of this region is membrane-embeddedwith five transmembrane helices (TMD0), while a small cytoplasmic loop of about 80amino acids (L0) connects this area to the core region. 29-32 Recent studies revealed thatthe TMD0 domain of ABCC1 does not play a crucial role in either the transport activityor the proper routing of the protein. However, the presence of the membrane-associatedcytoplasmic L0 region (together with the core region) is necessary for both the transportactivity and the proper intracellular routing of the protein. These studies indicate that theL0 region forms a distinct structural and functional domain, which interacts with themembrane and the core region of the MRP1 transporter. 33391