A stretch‐activated anion channel is up‐regulated by the malaria parasite <i>plasmodium falciparum</i>

Egée, Stéphane; Lapaix, Franck; Decherf, Gaëtan; Staines, Henry M.; Ellory, J. Clive; Doerig, Christian; Thomas, Serge

doi:10.1113/jphysiol.2002.022970

Cited by 92 publications

(107 citation statements)

References 18 publications

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“…anion conductance in uninfected non-CF red blood cells (17). Taken together, these data for the first time indicate a functional expression of CFTR in control but not in CFTR ⌬Phe-508/⌬Phe-508 red blood cells.…”

Section: Resultssupporting

confidence: 57%

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

Verloo

Kocken

Wel

et al. 2004

Journal of Biological Chemistry

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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.

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Section: Resultssupporting

confidence: 57%

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

Verloo

Kocken

Wel

et al. 2004

Journal of Biological Chemistry

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“…The buffy coat containing platelets and white cells was removed by suction after each wash. After the last wash, the cells were suspended at 50% hematocrit in RPMI medium 1640. P. falciparum clone 3D7 was grown in human RBCs as described previously (7,22). 5.…”

Section: Methodsmentioning

confidence: 99%

“…Recent whole-cell electrophysiological studies of human erythrocyte membrane in serum-free isotonic conditions showed that infection by P. falciparum activates, at the trophozoite stage, a membrane conductance 100-to 150-fold larger than in uninfected cells (6)(7)(8)(9). The typical electrophysiological signature of infection is characterized by whole-cell current-voltage (I-V) curves showing inward rectification [lower current at positive membrane potential (Vm) than at negative values], anion selectivity, and inhibition by furosemide and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB).…”

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confidence: 99%

Toward a unifying model of malaria-induced channel activity

Bouyer

Egée

Thomas³

2007

Proc. Natl. Acad. Sci. U.S.A.

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Infection of RBC by the malaria parasite Plasmodium falciparum activates, at the trophozoite stage, a membrane current 100-to 150-fold larger than in uninfected RBC. This current is carried by small anion channels initially described in supraphysiological ion concentrations (1.115 M Cl ؊ ) and named plasmodial surface anion channels (PSAC), suggesting their plasmodial origin. Our results obtained with physiological ion concentrations (0.145 M Cl ؊ ) support the notion that the parasite-induced channels represent enhanced activity versions of anion channels already present in uninfected RBCs. Among them, an 18-pS inwardly rectifying anion channel (IRC) and a 4-to 5-pS small conductance anion channel (SCC) were present in most single-channel recordings of infected membranes. The aim of this study was to clarify disparities in the reported electrophysiological data and to investigate possible technical reasons why these discrepancies have arisen. We demonstrate that PSAC is the supraphysiological correlate of the SCC and is inhibited by Zn 2؉ , suggesting that it is a ClC-2 channel. We show that in physiological solutions 80% of the membrane conductance in infected cells can be accounted for by IRC and 20% can be accounted for by SCC whereas in supraphysiological conditions the membrane conductance is almost exclusively carried by SCC (PSAC) because the IRC is functionally turned off.ionic channels ͉ new permeation pathways ͉ Plasmodium ͉ red blood cell P lasmodium falciparum-infected human RBCs possess parasite-induced new permeation pathways (1), which allow the uptake of nutrients and excretion of metabolic waste products. The properties of the new permeation pathways have been a major area of interest particularly in the context of whether they are possible antimalarial targets for selective inhibition and routes for drug delivery in future chemotherapies (2). They were originally defined, using nonelectrophysiological techniques, as having the general characteristics of anion channels (3-5).Recent whole-cell electrophysiological studies of human erythrocyte membrane in serum-free isotonic conditions showed that infection by P. falciparum activates, at the trophozoite stage, a membrane conductance 100-to 150-fold larger than in uninfected cells (6-9). The typical electrophysiological signature of infection is characterized by whole-cell current-voltage (I-V) curves showing inward rectification [lower current at positive membrane potential (Vm) than at negative values], anion selectivity, and inhibition by furosemide and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB). This whole-cell current is carried by anion channels, but the origin, number, molecular nature, and biophysical features of these channels remain controversial (10). Desai and coworkers (6,11,12), using the cell-attached configuration with 1 M choline chloride in bath and pipette solutions, described a 20-pS channel that they called plasmodial surface anion channel (PSAC) and considered as parasite-derived. They estimated PSAC's conductance at phy...

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“…Although several reports have suggested that PSAC activity results from the modification of host RBC proteins (13)(14)(15), none of these mutually exclusive proposals has been independently confirmed. In particular, we were unable to reproduce these reports despite intensive efforts (10).…”

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confidence: 98%

Plasmodial Surface Anion Channel-independent Phloridzin Resistance in Plasmodium falciparum

Desai

Alkhalil

Kang

et al. 2005

Journal of Biological Chemistry

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The plasmodial surface anion channel (PSAC) is an unusual ion channel induced on the human red blood cell membrane after infection with the malaria parasite, Plasmodium falciparum. Because PSAC is permeant to small metabolic precursors essential for parasite growth and is present on red blood cells infected with geographically divergent parasite isolates, it may be an ideal target for future antimalarial development. Here, we used chemically induced mutagenesis and known PSAC antagonists that inhibit in vitro parasite growth to examine whether resistance mutations in PSAC can be readily induced. Stable mutants resistant to phloridzin were generated and selected within 3 weeks after treatment with 1-methyl-3-nitro-1-nitrosoguanidine. These mutants were evaluated with osmotic lysis and electrophysiological transport assays, which indicate that PSAC inhibition by phloridzin is complex with at least two different modes of inhibition. Mutants resistant to the growth inhibitory effects of phloridzin expressed PSAC activity indistinguishable from that on sensitive parasites, indicating selection of resistance via mutations in one or more other parasite targets. Failure to induce mutations in PSAC activity is consistent with a highly constrained channel protein less susceptible to resistance mutations; whether this protein is parasiteor host-encoded remains to be determined.We recently used the cell-attached and whole cell patch clamp methods to identify an unusual ion channel on the red blood cell (RBC) 1 membrane of infected cells (1). This channel, the plasmodial surface anion channel (PSAC), has a number of unusual functional properties that distinguish it from known human channels. First, it accounts for increases in permeability to a range of solutes identified in many previous studies. PSAC is permeant to both anions (2) and organic solutes such as sugars (3), amino acids (4), purines (5), some vitamins (6), and a number of organic cations (7). Amazingly, although broadly permeant, it effectively excludes Na ϩ by Ͼ100,000-fold relative to Cl Ϫ . This combination, unparalleled in other known channels, permits osmotic stability of the infected RBC in serum while permitting the acquisition of diverse essential nutrients (8). PSAC achieves its stringent exclusion of Na ϩ through the combined effects of extracellular pore mouth cationic amines to repel extracellular cations and at least one weak binding site in its pore to favor bulky dehydrated ions over smaller ions (9).Another unusual feature of PSAC is its small single channel conductance of ϳ20 pS in 1.15 molar Cl Ϫ solutions (10); most other channels with broad selectivity profiles exhibit larger single channel conductances. A channel's chord conductance, calculated from measured current amplitudes at a range of imposed membrane potentials, quantitatively corresponds to the number of ions passing through the open channel per unit time. In terms of Eyring rate theory, this channel's small conductance reflects the one or more energetic barriers that each solute mo...

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A stretch‐activated anion channel is up‐regulated by the malaria parasite plasmodium falciparum

Cited by 92 publications

References 18 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

Toward a unifying model of malaria-induced channel activity

Plasmodial Surface Anion Channel-independent Phloridzin Resistance in Plasmodium falciparum

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