Plasmodium Induces Swelling-activated ClC-2 Anion Channels in the Host Erythrocyte

Huber, Stephan M.; Duranton, Christophe; Henke, Guido; Sand, Claudia van de; Heussler, Volker; Shumilina, Ekaterina; Sandu, Ciprian; Tanneur, Valérie; Brand, Verena; Kasinathan, Ravi S.; Lang, Karl S.; Kremsner, Peter G.; Hübner, Christian A.; Rust, Marco B.; Dedek, Karin; Jentsch, Thomas J.; Läng, Florian

doi:10.1074/jbc.m407618200

Cited by 80 publications

(88 citation statements)

References 48 publications

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“…The IRC can be activated by forskolin in intact noninfected cells and in RBCs of cystic fibrosis patients; it is able to transport ATP, and its membership of the ATP binding cassette family of anion channel was suggested (17). It is probable that the Zn 2ϩ -sensitive channel belongs to the ClC-2 family, in keeping with the observations of Lang's group (16), who found by immunoblotting that ClC-2 protein is expressed in human RBCs. However, with regard to slow gating of ClC-2 channel (18), further experiments are clearly needed before definitely identifying the SCC-PSAC as a ClC-2 channel.…”

Section: Discussionsupporting

confidence: 68%

“…They showed that two of the anion conductances exhibit inward rectification and provided evidence that one of them is attributable to the chloride channel ClC-2, sensitive to cell volume and inhibited by Zn 2ϩ (16); the third conductance exhibits outward rectification. This group also found that conductances similar to each of those seen in infected cells can be activated in uninfected erythrocytes by oxidation (14).…”

mentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 68%

mentioning

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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“…In contrast, another study found that Plasmodium vinckei induces a broad specificity, furosemide-sensitive pathway similar to PSAC and that it also upregulates the endogenous mouse RBC choline carrier (33). Electrophysiological studies of Plasmodium gallinaceuminfected chicken RBCs (36) and of Plasmodium bergheiinfected mouse RBCs (20) appear to support upregulation of endogenous channels, although achieved signal-to-noise ratios-calculated from solution compositions and reported seal resistances-were not adequate to rule out PSAC-like channels.…”

Section: ͼ Brmentioning

confidence: 86%

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

Lisk

Desai

2005

Eukaryot Cell

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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.

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“…Similar currents recorded in Plasmodium berghei-infected mouse erythrocytes were absent from plasmodiuminfected Clcn2 -/-red cells [23]. The relationship between this current and the 80 pS outwardly rectifying anion conductance upregulated in red cells of cystic fibrosis patients [58] remains unclear.…”

Section: Possible Identity Of Mediator(s) Of the Dids-insensitive Animentioning

confidence: 71%

“…The pipette was backfilled with pipette solution containing 100 μM nystatin, then front-filled with nystatin-free pipette solution. In a typical experiment, attainment of a 20 GΩ cell-attached seal was followed within ∼3 min by a decrease in pipette resistance to ∼3 GΩ, indicative of transition from cellattached to whole cell configuration as first reported in frog erythrocytes [6] and subsequently in human [22] and mouse red cells [23].…”

Section: Nystatin-permeabilized Whole Cell Patch Clamp Of Red Cellsmentioning

confidence: 99%

Reduced DIDS-sensitive chloride conductance in Ae1−/− mouse erythrocytes

Alper

Vandorpe

Peters

et al. 2008

Blood Cells, Molecules, and Diseases

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The resting membrane potential of the human erythrocyte is largely determined by a constitutive Cl -conductance ∼100-fold greater than the resting cation conductance. The 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS)-sensitive electroneutral Cl -transport mediated by the human erythroid Cl -/HCO 3 -exchanger, AE1 (SLC4A1, band 3) is ≥10,000-fold greater than can be accounted for by the Cl -conductance of the red cell. The molecular identities of conductive anion pathways across the red cell membrane remain poorly defined. We have examined red cell Cl -conductance in the Ae1 -/-mouse as a genetic test of the hypothesis that Ae1 mediates DIDSsensitive Cl -conductance in mouse red cells. We report here that wildtype mouse red cell membrane potential resembles that of human red cells in the predominance of its Cl -conductance. We show with four technical approaches that the DIDS-sensitive component of erythroid Cl -conductance is reduced or absent from Ae1 -/-red cells. These results are consistent with the hypothesis that the Ae1 anion exchanger polypeptide can operate infrequently in a conductive mode. However, the fragile red cell membrane of the Ae1 -/-mouse red cell exhibits reduced abundance or loss of multiple polypeptides. Thus, loss of one or more distinct, DIDS-sensitive anion channel polypeptide(s) from the Ae1 -/-red cell membrane cannot be ruled out as an explanation for the reduced DIDS-sensitive anion conductance.

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Plasmodium Induces Swelling-activated ClC-2 Anion Channels in the Host Erythrocyte

Cited by 80 publications

References 48 publications

Toward a unifying model of malaria-induced channel activity

Toward a unifying model of malaria-induced channel activity

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

Reduced DIDS-sensitive chloride conductance in Ae1−/− mouse erythrocytes

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