title: A blasticidin S-resistant Plasmodium falciparum mutant with a defective plasmodial surface anion channel.
abstract: Erythrocytes infected with malaria parasites exhibit marked increases in permeability to organic and inorganic solutes. The plasmodial surface anion channel (PSAC), an unusual voltage-dependent ion channel induced on the host membrane after infection, may play a central role in these permeability changes. Here, we identified a functional PSAC mutant through in vitro selection with blasticidin S. Resistance to blasticidin S was generated during culture and correlated with significant reductions in permeability to multiple solutes, consistent with uptake via a common pathway. Single channel recordings revealed marked changes in PSAC gating with the addition of a subconductance state not present in wild-type channels. The channel's selectivity profile and pharmacology also were significantly altered. Eventual loss of the mutant phenotype upon removal of selective pressure and slower growth of mutant parasites suggest that PSAC serves an important role in intracellular parasite survival. These findings provide solid evidence for the uptake of diverse solutes via PSAC and implicate one or more parasite genes in expression of this channel.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20852, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Hill
authors.forename: Ajay D
authors.initials: AD
authors.lastname: Pillai
authors.forename: Fatima
authors.initials: F
authors.lastname: Nawaz
authors.forename: Karen
authors.initials: K
authors.lastname: Hayton
authors.forename: Lanxuan
authors.initials: L
authors.lastname: Doan
authors.forename: Godfrey
authors.initials: G
authors.lastname: Lisk
authors.forename: Sanjay A
authors.initials: SA
authors.lastname: Desai
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D004351:Drug Resistance; D004594:Electrophysiology; D007473:Ion Channels / Q000378:metabolism*; D009705:Nucleosides / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D013997:Time Factors
chemical_list: D007473:Ion Channels; D009705:Nucleosides; C505335:surface anion channel protein, Plasmodium falciparum; C004500:blasticidin S