RT Journal Article SR Electronic T1 Solute Restriction Reveals an Essential Role for clag3-Associated Channels in Malaria Parasite Nutrient Acquisition JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1104 OP 1114 DO 10.1124/mol.112.081224 VO 82 IS 6 A1 Ajay D. Pillai A1 Wang Nguitragool A1 Brian Lyko A1 Keithlee Dolinta A1 Michelle M. Butler A1 Son T. Nguyen A1 Norton P. Peet A1 Terry L. Bowlin A1 Sanjay A. Desai YR 2012 UL http://molpharm.aspetjournals.org/content/82/6/1104.abstract AB 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.