title: Solute restriction reveals an essential role for clag3-associated channels in malaria parasite nutrient acquisition.
abstract: The plasmodial surface anion channel (PSAC) increases erythrocyte permeability to many solutes in malaria but has uncertain physiological significance. We used a PSAC inhibitor with different efficacies against channels from two Plasmodium falciparum parasite lines and found concordant effects on transport and in vitro parasite growth when external nutrient concentrations were reduced. Linkage analysis using this growth inhibition phenotype in the Dd2 × HB3 genetic cross mapped the clag3 genomic locus, consistent with a role for two clag3 genes in PSAC-mediated transport. Altered inhibitor efficacy, achieved through allelic exchange or expression switching between the clag3 genes, indicated that the inhibitor kills parasites through direct action on PSAC. In a parasite unable to undergo expression switching, the inhibitor selected for ectopic homologous recombination between the clag3 genes to increase the diversity of available channel isoforms. Broad-spectrum inhibitors, which presumably interact with conserved sites on the channel, also exhibited improved efficacy with nutrient restriction. These findings indicate that PSAC functions in nutrient acquisition for intracellular parasites. Although key questions regarding the channel and its biological role remain, antimalarial drug development targeting PSAC should be pursued.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ajay D
authors.initials: AD
authors.lastname: Pillai
authors.forename: Wang
authors.initials: W
authors.lastname: Nguitragool
authors.forename: Brian
authors.initials: B
authors.lastname: Lyko
authors.forename: Keithlee
authors.initials: K
authors.lastname: Dolinta
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Butler
authors.forename: Son T
authors.initials: ST
authors.lastname: Nguyen
authors.forename: Norton P
authors.initials: NP
authors.lastname: Peet
authors.forename: Terry L
authors.initials: TL
authors.lastname: Bowlin
authors.forename: Sanjay A
authors.initials: SA
authors.lastname: Desai
mesh_terms: D000818:Animals; D000838:Anions / Q000378:metabolism; D000962:Antimalarials / Q000494:pharmacology; D001692:Biological Transport; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000235:genetics; D057890:Epigenomics / Q000379:methods; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D006367:HeLa Cells; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008288:Malaria / Q000097:blood / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D000838:Anions; D000962:Antimalarials; D007473:Ion Channels; D015800:Protozoan Proteins; C502072:cytoadherence-linked asexual protein 3, Plasmodium falciparum; C505335:surface anion channel protein, Plasmodium falciparum