The Apicomplexan Molecular Physiology Section continued its studies of the plasmodial surface anion channel (PSAC) and made two significant contributions.? ? First, we identified and characterized the first PSAC mutant (PNAS 104:1063-1068, 2007). This mutant was generated by in vitro selection with blasticidin S, a toxin that reaches its intracellular target via permeation through PSAC. Because blasticidin S resistance correlated with reduced permeability to multiple solutes, we predicted there may be marked changes in PSAC. Single-channel and whole-cell electrophysiology confirmed this prediction by revealing altered channel gating, selectivity, pharmacology, and functional copy number/infected cell. Mutant parasites cultured without blasticidin S reverted to the wild-type channel phenotype and exhibited restored susceptibility to killing by blasticidin S. These findings 1) confirm that PSAC is the primary mechanism of organic solute uptake after infection because changes in PSAC affected the permeability of each solute, 2) implicate parasite genes in the expression of PSAC because human erythrocytes lack heritable genetic material, 3) provide a new approach to cloning PSACs gene, 4) reveal a new drug resistance mechanism in malaria parasites, and 5) suggest that PSAC serves an essential role for the intracellular parasite because a fitness cost was associated with blasticidin S resistance.? ? Second, we identified solute-inhibitor interactions within PSACs pore (Mol. Pharmacol. 71:1241-50, 2007). In this study, we found that phenyltrimethyl ammonium and isoleucine transport through PSAC were less effectively inhibited by known PSAC antagonists than the uptake of sorbitol and alanine. This observation was unexpected because all four solutes were thought to share a single transport mechanism. We excluded uptake via unrelated channels because specific PSAC inhibitors also exhibited solute-dependent affinities. Mixtures of permeating solutes, whole-cell electrophysiology, and temperature-dependence studies suggested that a single ion channel with two separate routes for permeating solutes is the most conservative explanation for our findings. Such a model may permit fine-tuning of PSACs unusual selectivity and allow the parasite to acquire a diverse collection of nutrients. These findings also suggest that PSAC antagonists must effectively block both routes to be suitable lead compounds for antimalarial drug development.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
United States
Zip Code
Lisk, Godfrey; Pain, Margaret; Gluzman, Ilya Y et al. (2008) Changes in the plasmodial surface anion channel reduce leupeptin uptake and can confer drug resistance in Plasmodium falciparum-infected erythrocytes. Antimicrob Agents Chemother 52:2346-54
Staines, Henry M; Alkhalil, Abdulnaser; Allen, Richard J et al. (2007) Electrophysiological studies of malaria parasite-infected erythrocytes: current status. Int J Parasitol 37:475-82
Alkhalil, Abdulnaser; Hill, David A; Desai, Sanjay A (2007) Babesia and plasmodia increase host erythrocyte permeability through distinct mechanisms. Cell Microbiol 9:851-60
Lisk, Godfrey; Scott, Seth; Solomon, Tsione et al. (2007) Solute-inhibitor interactions in the plasmodial surface anion channel reveal complexities in the transport process. Mol Pharmacol 71:1241-50
Hill, David A; Pillai, Ajay D; Nawaz, Fatima et al. (2007) A blasticidin S-resistant Plasmodium falciparum mutant with a defective plasmodial surface anion channel. Proc Natl Acad Sci U S A 104:1063-8
Lisk, Godfrey; Kang, Myungsa; Cohn, Jamieson V et al. (2006) Specific inhibition of the plasmodial surface anion channel by dantrolene. Eukaryot Cell 5:1882-93
Lisk, Godfrey; Desai, Sanjay A (2006) Improved perfusion conditions for patch-clamp recordings on human erythrocytes. Biochem Biophys Res Commun 347:158-65
Desai, Sanjay A (2005) Open and closed states of the plasmodial surface anion channel. Nanomedicine 1:58-66
Kang, Myungsa; Lisk, Godfrey; Hollingworth, Stephen et al. (2005) Malaria parasites are rapidly killed by dantrolene derivatives specific for the plasmodial surface anion channel. Mol Pharmacol 68:34-40
Desai, Sanjay A; Alkhalil, Abdulnaser; Kang, Myungsa et al. (2005) Plasmodial surface anion channel-independent phloridzin resistance in Plasmodium falciparum. J Biol Chem 280:16861-7

Showing the most recent 10 out of 18 publications