Extracellular lysines on the plasmodial surface anion channel involved in Na+ exclusion

Cohn, Jamieson V.; Alkhalil, Abdulnaser; Wagner, Marissa A.; Rajapandi, Thavamani; Desai, Sanjay A.

doi:10.1016/j.molbiopara.2003.08.001

Cited by 78 publications

(92 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Taken together, our data do not support the hypothesis raised by Desai et al (6) that the Plasmodium-activated inwardly rectifying ion channel (recently renamed PESAC (25,26)) adequately accounts for the parasite-induced increases in permeability to a broad range of solutes. Their hypothesis was based on the highly similar pharmacological profile of the inwardly rectifying chloride conductance and the new permeation pathway (6) and on the finding that the chloride conductivity of infected red blood cells, as calculated from patch clamp analysis, matched the chloride conductance calculated from chloride flux measurements (25).…”

Section: Discussioncontrasting

confidence: 99%

Plasmodium falciparum-activated Chloride Channels Are Defective in Erythrocytes from Cystic Fibrosis Patients

Verloo

Kocken

Wel

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

An inwardly rectifying anion channel in malaria-infected red blood cells has been proposed to function as the "new permeation pathway" for parasite nutrient acquisition. As the channel shares several properties with the cystic fibrosis transmembrane conductance regulator (CFTR), we tested their interrelationship by wholecell current measurements in Plasmodium falciparuminfected and uninfected red blood cells from control and cystic fibrosis (CF) patients. A CFTR-like linear chloride conductance as well as a malaria parasite-induced and a shrinkage-activated endogenous inwardly rectifying chloride conductance with properties identical to the malaria-induced channel were all found to be defective in CF erythrocytes. Surprisingly, the absence of the inwardly rectifying chloride conductance in CF erythrocytes had no gross effect on in vitro parasite growth or new permeation pathway activity, supporting an argument against a close association between the Plasmodium-activated chloride channel and the new permeation pathway. The functional expression of CFTR in red blood cells opens new perspectives to exploit the erythrocyte as a readily available cell type in electrophysiological, diagnostic, and therapeutic studies of CF.

show abstract

Section: Discussioncontrasting

confidence: 99%

Plasmodium falciparum-activated Chloride Channels Are Defective in Erythrocytes from Cystic Fibrosis Patients

Verloo

Kocken

Wel

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…1E). Both this list of solutes and estimates of their absolute permeabilities parallel previous measurements in the P. falciparum-human RBC system (5,17,38), suggesting PSAC-like channels on P. knowlesi-infected rhesus RBCs.…”

supporting

confidence: 80%

“…Another surprising selectivity feature is PSAC's ability to exclude Na ϩ by more than 100,000-fold relative to Cl Ϫ despite broad permeability to organic solutes of either net positive or negative charge (5).…”

Section: ͼ Brmentioning

confidence: 99%

The Plasmodial Surface Anion Channel Is Functionally Conserved in Divergent Malaria Parasites

Lisk

Desai

2005

Eukaryot Cell

Self Cite

View full text Add to dashboard Cite

The plasmodial surface anion channel (PSAC), a novel ion channel induced on human erythrocytes infected with Plasmodium falciparum, mediates increased permeability to nutrients and presumably supports intracellular parasite growth. Isotope flux studies indicate that other malaria parasites also increase the permeability of their host erythrocytes, but the precise mechanisms are unknown. Channels similar to PSAC or alternative mechanisms, such as the upregulation of endogenous host transporters, might fulfill parasite nutrient demands. Here we evaluated these possibilities with rhesus monkey erythrocytes infected with Plasmodium knowlesi, a parasite phylogenetically distant from P. falciparum. Tracer flux and osmotic fragility studies revealed dramatically increased permeabilities paralleling changes seen after P. falciparum infection. Patchclamp of P. knowlesi-infected rhesus erythrocytes revealed an anion channel with striking similarities to PSAC: its conductance, voltage-dependent gating, pharmacology, selectivity, and copy number per infected cell were nearly identical. Our findings implicate a family of unusual anion channels highly conserved on erythrocytes infected with various malaria parasites. Together with PSAC's exposed location on the host cell surface and its central role in transport changes after infection, this conservation supports development of antimalarial drugs against the PSAC family.

show abstract

“…Those workers also determined that the ionic strength effect was primarily via effects on the inhibitor association rate constant, a finding which suggested a detailed mechanism of inhibitor action on the channel. While similar studies with PSAC must wait for both the cloning of its gene(s) and the development of a suitable heterologous expression system, the ionic strength effect on dantrolene affinity is most conservatively explained by interaction with charged residues at the channel extracellular face, some of which have been identified using covalent modification with N-hydroxysulfosuccinimide esters (8). Alternative explanations are unlikely because neither ionic strength nor Cl Ϫ concentration affects the affinity of furosemide (1) or phloridzin (11).…”

Section: Discussionmentioning

confidence: 99%

Specific Inhibition of the Plasmodial Surface Anion Channel by Dantrolene

et al. 2006

Self Cite

View full text Add to dashboard Cite

The plasmodial surface anion channel (PSAC), induced on human erythrocytes by the malaria parasite Plasmodium falciparum, is an important target for antimalarial drug development because it may contribute to parasite nutrient acquisition. However, known antagonists of this channel are quite nonspecific, inhibiting many other channels and carriers. This lack of specificity not only complicates drug development but also raises doubts about the exact role of PSAC in the well-known parasite-induced permeability changes. We recently identified a family of new PSAC antagonists structurally related to dantrolene, an antagonist of muscle Ca ؉؉ release channels. Here, we explored the mechanism of dantrolene's actions on parasite-induced permeability changes. We found that dantrolene inhibits the increased permeabilities of sorbitol, two amino acids, an organic cation, and hypoxanthine, suggesting a common pathway shared by these diverse solutes. It also produced parallel reductions in PSAC single-channel and whole-cell Cl ؊ currents. In contrast to its effect on parasite-induced permeabilities, dantrolene had no measurable effect on five other classes of anion channels, allaying concerns of poor specificity inherent to other known antagonists. Our studies indicate that dantrolene binds PSAC at an extracellular site distinct from the pore, where it inhibits the conformational changes required for channel gating. Its affinity for this site depends on ionic strength, implicating electrostatic interactions in dantrolene binding. In addition to the potential therapeutic applications of its derivatives, dantrolene's specificity and its defined mechanism of action on PSAC make it a useful tool for transport studies of infected erythrocytes.

show abstract

Extracellular lysines on the plasmodial surface anion channel involved in Na+ exclusion

Cited by 78 publications

References 22 publications

Plasmodium falciparum-activated Chloride Channels Are Defective in Erythrocytes from Cystic Fibrosis Patients

Plasmodium falciparum-activated Chloride Channels Are Defective in Erythrocytes from Cystic Fibrosis Patients

The Plasmodial Surface Anion Channel Is Functionally Conserved in Divergent Malaria Parasites

Specific Inhibition of the Plasmodial Surface Anion Channel by Dantrolene

Contact Info

Product

Resources

About