Abstract
The plasmodial surface anion channel (PSAC) is an unusual ion channel induced on the human red blood cell membrane after infection with the malaria parasite, Plasmodium falciparum. Because PSAC is permeant to small metabolic precursors essential for parasite growth and is present on red blood cells infected with geographically divergent parasite isolates, it may be an ideal target for future antimalarial development. Here, we used chemically induced mutagenesis and known PSAC antagonists that inhibit in vitro parasite growth to examine whether resistance mutations in PSAC can be readily induced. Stable mutants resistant to phloridzin were generated and selected within 3 weeks after treatment with 1-methyl-3-nitro-1-nitrosoguanidine. These mutants were evaluated with osmotic lysis and electrophysiological transport assays, which indicate that PSAC inhibition by phloridzin is complex with at least two different modes of inhibition. Mutants resistant to the growth inhibitory effects of phloridzin expressed PSAC activity indistinguishable from that on sensitive parasites, indicating selection of resistance via mutations in one or more other parasite targets. Failure to induce mutations in PSAC activity is consistent with a highly constrained channel protein less susceptible to resistance mutations; whether this protein is parasite- or host-encoded remains to be determined.
Highlights
Through the combined effects of extracellular pore mouth cationic amines to repel extracellular cations and at least one weak binding site in its pore to favor bulky dehydrated ions over smaller ions [9]
In light of the high permeability of plasmodial surface anion channel (PSAC) to diverse solutes needed for parasite growth, the most appealing proposal is that this channel serves as the first step in a sequential diffusive pathway for nutrient acquisition by the intracellular parasite [1]
Waste products such as lactateϪ, a toxic metabolite made by the parasite, can be removed from the cell by transport in the reverse direction, first through a lactate carrier on the parasite plasma membrane [27] and through giant non-selective channels on the parasitophorous vacuolar membrane [28, 29] and across the host membrane through PSAC
Summary
Through the combined effects of extracellular pore mouth cationic amines to repel extracellular cations and at least one weak binding site in its pore to favor bulky dehydrated ions over smaller ions [9] Another unusual feature of PSAC is its small single channel conductance of ϳ20 pS in 1.15 molar ClϪ solutions [10]; most other channels with broad selectivity profiles exhibit larger single channel conductances. Despite the nearly invariant membrane potential of human RBCs after infection, permeation through PSAC is voltage-dependent Both whole cell and single channel recordings reveal significantly smaller absolute currents at membrane potentials (Vm) of ϩ100 millivolts than of Ϫ100 millivolts despite equal but opposite driving forces for ion movement. Channels exhibiting this phenomenon were often referred to as “inward rectifying” voltage-dependent channels.
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