title: Altered plasmodial surface anion channel activity and in vitro resistance to permeating antimalarial compounds.
abstract: Erythrocytes infected with malaria parasites have increased permeability to various solutes. These changes may be mediated by an unusual small conductance ion channel known as the plasmodial surface anion channel (PSAC). While channel activity benefits the parasite by permitting nutrient acquisition, it can also be detrimental because water-soluble antimalarials may more readily access their parasite targets via this channel. Recently, two such toxins, blasticidin S and leupeptin, were used to select mutant parasites with altered PSAC activities, suggesting acquired resistance via reduced channel-mediated toxin uptake. Surprisingly, although these toxins have similar structures and charge, we now show that reduced permeability of one does not protect the intracellular parasite from the other. Leupeptin accumulation in the blasticidin S-resistant mutant was relatively preserved, consistent with retained in vitro susceptibility to leupeptin. Subsequent in vitro selection with both toxins generated a double mutant parasite having additional changes in PSAC, implicating an antimalarial resistance mechanism for water-soluble drugs requiring channel-mediated uptake at the erythrocyte membrane. Characterization of these mutants revealed a single conserved channel on each mutant, albeit with distinct gating properties. These findings are consistent with a shared channel that mediates uptake of ions, nutrients and toxins. This channel's gating and selectivity properties can be modified in response to in vitro selective pressure.
authors.affiliation: The Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.
authors.forename: Godfrey
authors.initials: G
authors.lastname: Lisk
authors.forename: Margaret
authors.initials: M
authors.lastname: Pain
authors.forename: Morgan
authors.initials: M
authors.lastname: Sellers
authors.forename: Philip A
authors.initials: PA
authors.lastname: Gurnev
authors.forename: Ajay D
authors.initials: AD
authors.lastname: Pillai
authors.forename: Sergey M
authors.initials: SM
authors.lastname: Bezrukov
authors.forename: Sanjay A
authors.initials: SA
authors.lastname: Desai
mesh_terms: D000838:Anions; D000962:Antimalarials / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D004351:Drug Resistance; D004910:Erythrocyte Membrane / Q000378:metabolism; D015640:Ion Channel Gating; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D009154:Mutation; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000838:Anions; D000962:Antimalarials; D007473:Ion Channels
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