Na⁺ Regulation in the Malaria Parasite Plasmodium falciparum Involves the Cation ATPase PfATP4 and Is a Target of the Spiroindolone Antimalarials
2013
Spillman, Natalie J. | Allen, Richard J.W. | McNamara, Case W. | Yeung, Bryan K.S. | Winzeler, Elizabeth A. | Diagana, Thierry T. | Kirk, Kiaran
The malaria parasite Plasmodium falciparum establishes in the host erythrocyte plasma membrane new permeability pathways that mediate nutrient uptake into the infected cell. These pathways simultaneously allow Na⁺ influx, causing [Na⁺] in the infected erythrocyte cytosol to increase to high levels. The intraerythrocytic parasite itself maintains a low cytosolic [Na⁺] via unknown mechanisms. Here we present evidence that the intraerythrocytic parasite actively extrudes Na⁺ against an inward gradient via PfATP4, a parasite plasma membrane protein with sequence similarities to Na⁺-ATPases of lower eukaryotes. Mutations in PfATP4 confer resistance to a potent class of antimalarials, the spiroindolones. Consistent with this, the spiroindolones cause a profound disruption in parasite Na⁺ homeostasis, which is attenuated in parasites bearing resistance-conferring mutations in PfATP4. The mutant parasites also show some impairment of Na⁺ regulation. Taken together, our results are consistent with PfATP4 being a Na⁺ efflux ATPase and a target of the spiroindolones.
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