Na+ regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials
Date
2013
Authors
Spillman, Natalie
Allen, Richard
McNamara, Case W.
Yeung, Bryan K.S.
Winzeler, Elizabeth A.
Diagana, Thierry T.
Kirk, Kiaran
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Volume Title
Publisher
Cell Press
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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Keywords
Keywords: adenosine triphosphatase; adenosine triphosphatase PfATP4; antimalarial agent; membrane protein; nitd 138; nitd 139; nitd 246; nitd 247; sodium; spiroindolone; unclassified drug; article; controlled study; drug potency; drug structure; gene mutation; home
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Source
Cell Host and Microbe
Type
Journal article
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2037-12-31