Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials

Cell Host Microbe. 2013 Feb 13;13(2):227-37. doi: 10.1016/j.chom.2012.12.006.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Antimalarials / pharmacology*
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism*
  • Drug Resistance
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Erythrocyte Membrane / drug effects
  • Erythrocyte Membrane / metabolism
  • Erythrocytes / metabolism
  • Erythrocytes / parasitology
  • Homeostasis
  • Humans
  • Indoles / pharmacology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mutation
  • Ouabain / pharmacology
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Plasmodium falciparum / genetics
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism
  • Sodium / metabolism*
  • Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors
  • Sodium-Potassium-Exchanging ATPase / metabolism*
  • Spiro Compounds / pharmacology
  • Trophozoites / drug effects
  • Trophozoites / metabolism

Substances

  • Antimalarials
  • Cation Transport Proteins
  • Enzyme Inhibitors
  • Indoles
  • Membrane Proteins
  • NITD 609
  • Protozoan Proteins
  • Spiro Compounds
  • Ouabain
  • Sodium
  • Adenosine Triphosphatases
  • sodium-translocating ATPase
  • Sodium-Potassium-Exchanging ATPase