A P-glycoprotein homologue of Plasmodium falciparum is localized on the digestive vacuole.

Abstract

Abstract. Resistance to chloroquine in Plasmodium falciparum bears a striking similarity to the multi-drug resistance (MDR) phenotype of mammalian tumor cells which is mediated by overexpression of P-glycoprotein. We show here that the P. falciparum homologue of the P-glycoprotein (Pghl) is a 160,000-D protein that is expressed throughout the asexual erythrocytic life cycle of the parasite. Quantitative immunoblotting analysis has shown that the protein is expressed at approximately equal levels in chloroquine resistant and sensitive isolates suggesting that overexpression of Pghl is not essential for chloroquine resistance. The chloroquine-resistant cloned line FAC8 however, does express approximately threefold more Pghl protein than other isolates which is most likely because of the increased pfmdrl gene copy number present in this isolate. Immunofluorescence and immunoelectron microscopy has demonstrated that Pghl is localized on the membrane of the digestive vacuole of mature parasites. This subcellular localization suggests that Pghl may modulate intracellular chloroquine concentrations and has important implications for the normal physiological function of this protein.

Chloroquine Resistance Modulated in Vitro by Expression Levels of the Plasmodium falciparum Chloroquine Resistance Transporter

“…Thus, point mutations and expression levels of both pfcrt and pfmdr1 have now been found to have an impact on the degree of CQ susceptibility. Both genes encode proteins localized on the membrane of the DV (19,42,56), the organelle wherein CQ exerts its activity, implying that altered functional properties of the DV membrane are key to the CQR mechanism.…”

Pfmdr1 gene polymorphism of Plasmodium falciparum isolates from asymptomatic individuals of Dienga, southeastern Gabon

“…Pfmdr1 is an ATP cassette protein located on the parasite's food vacuole. Indeed, the mutations in this gene reduce the parasite's sensitivity to anti-malarial drugs [17]. The therapeutic failures following ACTs treatments were associated with the selection of N86, 184F and D1246 (NFD genotype), in the Pfmdr1 gene [18].…”

pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum

“…Although the molecular basis for the resistance of P. falciparum to many drugs has not yet been fully characterized, there is strong in vitro evidence that P. falciparum chloroquine resistance transporter (PfCRT) and Pglycoprotein homologue 1 (Pgh1), two proteins localized to the parasite's digestive vacuole membrane (Cowman et al ., 1991;Fidock et al ., 2000), can play important roles in determining sensitivity to multiple antimalarials including chloroquine (CQ), the most widely used and extensively studied antimalarial. Laboratory studies have shown that transfection of chloroquine-sensitive (CQS) parasites with the pfcrt gene from several different chloroquine-resistant (CQR) strains can confer resistance to CQ, and increase susceptibility to quinine, mefloquine and artemisinin (Fidock et al ., 2000;Sidhu et al ., 2002).…”