Title |
Na+ Regulation in the Malaria Parasite Plasmodium falciparum Involves the Cation ATPase PfATP4 and Is a Target of the Spiroindolone Antimalarials
|
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Published in |
Cell Host & Microbe (Science Direct), February 2013
|
DOI | 10.1016/j.chom.2012.12.006 |
Pubmed ID | |
Authors |
Natalie J. Spillman, Richard J.W. Allen, Case W. McNamara, Bryan K.S. Yeung, Elizabeth A. Winzeler, Thierry T. Diagana, Kiaran Kirk |
Abstract |
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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