P-glycoprotein and ‘lipid rafts’: some ambiguous mutual relationships (floating on them, building them or meeting them by chance?)

Abstract

P-glycoprotein (P-gp) is an active membrane transporter responsible for cell detoxification against numerous amphiphilic compounds, leading to multidrug resistance in tumor cells. It displays entangled connections with its membrane environment since it recognizes its substrates within the cytosolic leaflet and it also translocates some endogenous lipids to the exoplasmic leaflet. Regarding its relationships with membrane microdomains, 'lipid rafts', a literature analysis concludes that (i) P-gp also exists in rafts and non-raft membrane domains, depending on the cell considered, the experimental conditions and the method used to test it; (ii) cholesterol has a positive influence on P-gp function, and this may be a direct effect of the free cholesterol present in membrane or an indirect effect mediated by the cholesterol-enriched microdomains; (iii) when present in rafts, P-gp interacts with protein partners regulating its activity; (iv) P-gp is a lipid translocase that handles the raft-constituting lipids with particular efficiency, and it also influences membrane trafficking in the cell.

Short Ligands Affect Modes of QD Uptake and Elimination in Human Cells

“…35 P-gps have been found within lipid raft membrane domains. Cholesterol was established as one of the modulators of P-gp functions, suggesting the ability of cells to eliminate QDs being, at least in part, dependent on their cholesterol content.…”

“…34 In view of its high rate and broad substrate range, the P-glycoprotein (P-gp) transporter is likely to be involved in QD elimination. 35 To assess the potential role of P-gp in QD elimination, we used two pharmacological agents, elacridar and rifampin, a P-gp inhibitor and a P-gp inducer, respectively. 36,37 The types of QDs employed and the uptake/elimination mechanisms probed are depicted schematically in Figure 1.…”

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

“…Both ABCB1 and ABCG2 have been reported to reside in detergentinsoluble rafts (Ismair et al, 2009;Orlowski, Martin, & Escargueil, 2006;Radeva, Perabo, & Sharom, 2005;Storch, Ehehalt, Haefeli, & Weiss, 2007) and in close interaction with cholesterol and caveolin. In the canalicular membranes of hepatocytes, several ABC transporters, including ABCB4 (MDR3), ABCB11 (BSEP, S-P-gp), ABCC2 (MRP2), and ABCG5/G8, have also been shown to reside in raft domains (Ismair et al, 2009).…”

“…It is important to note that ABCB1 is in a mutual relationship with its membrane environment, that is, not only the membrane lipids alter the function of ABCB1 but this protein may actively modify its lipid environment (for reviews, see Denning & Beckstein, 2013;Orlowski et al, 2006;Peetla, Vijayaraghavalu, & Labhasetwar, 2013;Pohl, Devaux, & Herrmann, 2005;Sharom, 2014). ABCG2 is less characterized in this respect, but lipid interactions certainly affect its function.…”

“…ABCB1 has been reported to reside in Triton X-100-resistant rafts (Ismair et al, 2009;Orlowski et al, 2006) or in Brij 96-resistant rafts (Radeva et al, 2005), although ABCB1 was found to be an active drug transporter both in raft and in nonraft regions (Bucher, Besse, Kamau, Wunderli-Allenspach, & Kramer, 2005). Still, recent studies, examining the ratio of active state conformations of ABCB1 by the conformation sensitive UIC2 antibody, indicate that this protein may be more active in cholesterol-rich, caveolin-positive regions and thus may be regulated by factors altering raft assembly (Bacso et al, 2004).…”