title: Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials.
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.
authors: Research School of Biology, The Australian National University, Canberra, ACT 0200, Australia.
authors: Natalie J
authors: NJ
authors: Spillman
authors: Richard J W
authors: RJ
authors: Allen
authors: Case W
authors: CW
authors: McNamara
authors: Bryan K S
authors: BK
authors: Yeung
authors: Elizabeth A
authors: EA
authors: Winzeler
authors: Thierry T
authors: TT
authors: Diagana
authors: Kiaran
authors: K
authors: Kirk
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000962:Antimalarials / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D006706:Homeostasis; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010042:Ouabain / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013141:Spiro Compounds / Q000494:pharmacology; D053058:Trophozoites / Q000187:drug effects / Q000378:metabolism
chemical_list: D000962:Antimalarials; D027682:Cation Transport Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D008565:Membrane Proteins; C552304:NITD 609; D015800:Protozoan Proteins; D013141:Spiro Compounds; D010042:Ouabain; D012964:Sodium; D000251:Adenosine Triphosphatases; C021838:sodium-translocating ATPase; D000254:Sodium-Potassium-Exchanging ATPase