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Up-regulation of the membrane-bound efflux pump P-glycoprotein (P-gp) is associated with the phenomenon of multidrug-resistance in pathogenic organisms, including protozoan parasites. In addition, P-gp plays a role in normal physiological processes, however our understanding of these P-gp functions remains limited. In this study we investigated the effects of the P-gp inhibitor GF120918 in  Toxoplasma gondii , a model apicomplexan parasite and an important human pathogen. We found that GF120918 treatment severely inhibited parasite invasion and replication. Further analyses of the molecular mechanisms involved revealed that the P-gp inhibitor modulated parasite motility, microneme secretion and egress from the host cell, all cellular processes known to depend on Ca 2+  signaling in the parasite. In support of a potential role of P-gp in Ca 2+ -mediated processes, immunoelectron and fluorescence microscopy showed that  T. gondii  P-gp was localized in acidocalcisomes, the major Ca 2+  storage in the parasite, at the plasma membrane, and in the intravacuolar tubular network. In addition, metabolic labeling of extracellular parasites revealed that inhibition or down-regulation of  T. gondii  P-gp resulted in aberrant lipid synthesis. These results suggest a crucial role of  T. gondii  P-gp in essential processes of the parasite biology and further validate the potential of P-gp activity as a target for drug development.

The P-glycoprotein Inhibitor GF120918 Modulates Ca2+-Dependent Processes and Lipid Metabolism in Toxoplasma Gondii