ATP-binding cassette (ABC) transporters are known to be important factors in multidrug resistance of tumor cells. Lipid rafts have been implicated in their localization in the plasma membrane, where they function as drug efflux pumps. This specific localization in rafts may support the activity of ABC/Abc transporters. This raises questions regarding the nature and composition of the lipid rafts that harbor ABC/Abc transporters and the dependence of ABC/Abc transporters—concerning their localization and activity—on lipid raft constituents. Here we review our work of the past 10 years aimed at evaluating whether ABC/Abc transporters are dependent on a particular membrane environment for their function. What is the nature of this membrane environment and which of the lipid raft constituents are important for this dependency? It turns out that cortical actin is of major importance for stabilizing the localization and function of the ABC/Abc transporter, provided it is localized in an actin-dependent subtype of lipid rafts, as is the case for human ABCC1/multidrug resistance-related protein 1 (MRP1) and rodent Abcc1/Mrp1 but not human ABCB1/P-glycoprotein (PGP). On the other hand, sphingolipids do not appear to be modulators of ABCC1/MRP1 (or Abcc1/Mrp1), even though they are coregulated during drug resistance development. 1. Introduction The family of ATP-binding cassette (ABC/Abc) transporters is an important group of membrane-associated proteins that serve as transmembrane transporters for various substrates, including cytostatics employed to kill tumor cells. There is a body of evidence indicating that these transporters are associated with lipid rafts, as reviewed in a number of papers (e.g., [1–3]). In most studies lipid rafts were isolated biochemically, initially employing detergents and later also using detergent-free approaches. The membrane domains isolated using detergents were named detergent-resistant membranes (DRM) among other names. Likewise, in the case of detergent-free isolation we refer to these membrane domains as detergent-free membranes (DFM). The association of ABC/Abc transporters with these membrane domains raises the question whether this has consequences for the activity of these proteins as drug efflux pumps. Indeed, the membrane environment may contribute to optimal activity of the transporter. Moreover, if there is indeed a functional consequence of being in a lipid raft, it is challenging to investigate which components of lipid rafts may be instrumental as modulators of ABC activity. Such lipid raft components may function
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