The Apicomplexan Molecular Physiology Unit conducts basic research on the transport of ions and nutrients across various membranes of human red blood cells infected with malaria parasites. This work incorporates molecular biology and informatics, protein and lipid biochemistry, immunofluorescent localization of membrane proteins, various transport assays, biophysics, high-throughput screening of compound libraries, and examination of structure-activity relationships for small molecule inhibitors. We recently used electrophysiological methods to identify an unusual ion channel on human red blood cells infected with P. falciparum, which causes the deadliest form of malaria. This channel, the plasmodial surface anion channel (PSAC), is present at 1000 copies/cell, has unusual gating properties, and is permeable to a range of anions and nutrients known to be required for parasite growth. We proposed that PSAC mediates the first step in a sequential diffusive pathway of nutrient acquisition. Current projects in the lab include: 1) characterizing the mechanism of permeation through PSAC, 2) developing and testing specific PSAC blockers that may function as future antimalarials, 3) cloning the gene(s) encoding PSAC and other transporters, and 4) heterologous expression of these transporters. These projects aim to probe how PSAC achieves its unusual functional properties, to understand the parasite's cell biology and physiology, and to develop new strategies for the control of malaria. In the past fiscal year, the lab made several fundamental contributions to this important field. Most importantly, we addressed debates about how many different ion channels are induced on red blood cells infected with the malaria parasite. Measurements with isotope flux, osmotic lysis transport assays, and two independent configurations of patch-clamp indicate that a single ion channel, PSAC, can adequately account for the increased uptake of various small solutes. We also identified, for the first time, polymorphisms in PSAC gating behavior when red cells are cultured with geographically distinct parasite isolates, suggesting that PSAC is parasite-encoded. In a separate study, we examined PSAC's broad selectivity for diverse nutrient solutes in spite of its very low permeability to sodium ions. We found that this combination, unparalleled by any known human channel, is largely achieved by lysine residues in or near PSAC?s extracellular pore mouth. These functional studies have important implications for our understanding of how solutes permeate through PSAC, for insights into parasite biology, and for drug development against novel parasite targets.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Intramural Research (Z01)
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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

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