Characterization of permeation pathways appearing in the host membrane of Plasmodium falciparum infected red blood cells

Ginsburg, Hagaï; Kutner, Shirley; Krugliak, Miriam; Cabantchik, Z. I.

doi:10.1016/0166-6851(85)90059-3

Cited by 200 publications

(163 citation statements)

References 16 publications

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“…Infection of human red blood cells (RBCs) with the malaria parasite Plasmodium falciparum, leads to markedly increased uptake of anions (28), amino acids (6), sugars (21), purines (57), vitamins (50), and precursors for phospholipid biosynthesis (2). Although these permeability changes have been known for more that 50 years (43) and are proposed to function in nutrient acquisition from serum (12), the precise molecular mechanism for uptake remains under debate.…”

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confidence: 99%

Specific Inhibition of the Plasmodial Surface Anion Channel by Dantrolene

et al. 2006

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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.

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Specific Inhibition of the Plasmodial Surface Anion Channel by Dantrolene

et al. 2006

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“…In addition, the parasite interacts with its host cell and its environment by exporting a membrane network into the cytoplasm of its host cell and by inserting a number of proteins in the erythrocyte plasma membrane (3). As a result of these changes P. falciparum-infected erythrocytes show abnormally high permeability toward amino acids (1), sugars and polyols (2), purines (4), cations (5,6), and anions (7,8). The mechanism responsible for this increased permeability has a strong preference for anions over cations and is blocked by drugs known to inhibit anion-selective channels (9).…”

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confidence: 99%

“…The asexual development of malaria parasites inside the erythrocyte is accompanied by changes in the composition, structure, and function of the host cell membrane and cytoplasm (1,2). Upon invasion of the erythrocyte, the malaria parasite establishes a parasitophorous vacuole inside which it develops.…”

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A Malaria Parasite-encoded Vacuolar H+-ATPase Is Targeted to the Host Erythrocyte

Marchesini

Vieira

Luo

et al. 2005

Journal of Biological Chemistry

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The asexual development of malaria parasites inside the erythrocyte is accompanied by changes in the composition, structure, and function of the host cell membrane and cytoplasm. The parasite exports a membrane network into the host cytoplasm and several proteins that are inserted into the erythrocyte membrane, although none of these proteins has been shown to have enzymatic activity. We report here that a functional malaria parasite-encoded vacuolar (V)-H ؉ -ATPase is exported to the erythrocyte and localized in membranous structures and in the plasma membrane of the infected erythrocyte. This localization was determined by separation of parasite and erythrocyte membranes and determination of enzyme marker activities and by immunofluorescence microscopy assays using antibodies against the B subunit of the malarial V-H ؉ -ATPase and erythrocyte (spectrins) and parasite (merozoite surface protein 1) markers. Our results suggest that this pump has a role in the maintenance of the intracellular pH (pH i ) of the infected erythrocyte. Our results also indicate that although the pH i maintained by the V-H ؉ -ATPase is important for maximum uptake of small metabolites at equilibrium, it does not appear to affect transport across the erythrocyte membrane and is, therefore, not involved in the previously described phenomenon of increased permeability of infected erythrocytes that is sensitive to chloride channel inhibitors (new permeation pathway). This constitutes the first report of the presence of a functional enzyme of parasite origin in the plasma membrane of its host.Plasmodium falciparum, one of the agents responsible for malaria, is an obligate intracellular parasite belonging to the phylum Apicomplexa. The asexual development of malaria parasites inside the erythrocyte is accompanied by changes in the composition, structure, and function of the host cell membrane and cytoplasm (1, 2). Upon invasion of the erythrocyte, the malaria parasite establishes a parasitophorous vacuole inside which it develops. In addition, the parasite interacts with its host cell and its environment by exporting a membrane network into the cytoplasm of its host cell and by inserting a number of proteins in the erythrocyte plasma membrane (3). As a result of these changes P. falciparum-infected erythrocytes show abnormally high permeability toward amino acids (1), sugars and polyols (2), purines (4), cations (5, 6), and anions (7,8). The mechanism responsible for this increased permeability has a strong preference for anions over cations and is blocked by drugs known to inhibit anion-selective channels (9). The increased permeability, therefore, appears to be the result of the parasite activating or inserting an anion-selective channel in the membrane of the erythrocytes (9). Electrophysiological evidence for the presence of an anionselective channel in the plasma membrane of P. falciparum-infected erythrocytes (10) supports this proposal (9). This channel has a high permeability to chloride ions, but it is not known whether it is encod...

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“…[1][2][3][4][5] The increased permeability facilitates the uptake into the infected cell of several key nutrients, [6][7][8] as well as the uptake of various antiparasitic agents. [8][9][10][11][12] Parasiteinduced pathways also mediate both the efflux of metabolic wastes, 6,13 and a marked change in the ionic composition of the host cell cytosol.…”

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confidence: 99%

“…Human erythrocytes have a low basal permeability to glutamate; however, the amino acid readily enters P falciparum-infected erythrocytes. 1,2,27,28 Here we show that arsenite-treatment of (uninfected) human erythrocytes results in the activation of a high-affinity, Na ϩ -dependent glutamate transport pathway, which has the functional characteristics of members of the "excitatory amino acid transporter" (EAAT) family. 29,30 An analysis of the uptake of glutamate into P falciparum-infected erythrocytes revealed the presence of both low and high-affinity components.…”

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Chemical activation of a high-affinity glutamate transporter in human erythrocytes and its implications for malaria-parasite–induced glutamate uptake

Winterberg

Rajendran

Baumeister

et al. 2012

Blood

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IntroductionIt has long been recognized that after infection of the human erythrocyte by the malaria parasite Plasmodium falciparum, the host cell membrane undergoes a profound increase in its permeability to a diverse range of low molecular weight solutes including amino acids, sugars, nucleosides, and a range of organic and inorganic anions and cations. [1][2][3][4][5] The increased permeability facilitates the uptake into the infected cell of several key nutrients, 6-8 as well as the uptake of various antiparasitic agents. [8][9][10][11][12] Parasiteinduced pathways also mediate both the efflux of metabolic wastes, 6,13 and a marked change in the ionic composition of the host cell cytosol. 4,14 The question of the number and origin of the pathways underpinning the parasite-induced increase in host erythrocyte permeability has been a vexed one. Subjecting uninfected human erythrocytes to oxidative stress, 15,16 or to protein kinase Amediated protein phosphorylation, [17][18][19] results in the activation of membrane channels that confer on the membrane of the uninfected cell, similar to permeability characteristics seen in the infected cell. This is consistent with at least some part of the parasite-induced permeability being attributed to the activation of endogenous host cell proteins. A recent paper has proposed a central role for an endogenous erythrocyte benzodiazopene receptor/voltagedependent anion channel 20 in forming the parasite-induced pathways. At the same time, there is evidence for the involvement of parasite-encoded proteins. After earlier observations of significant parasite-strain-specific differences in the electrophysiologic characteristics of parasite-induced ion conductances 21,22 and the identification of parasite strains for which the infected erythrocyte has reduced permeability to various cytotoxic agents, 10,11,23 Desai and colleagues have demonstrated a role for parasite-encoded "clag3" proteins in the formation of parasite-induced channels. 24 Whether these proteins themselves form part of the channels is not yet clear.Exposure of cells to arsenite is known both to induce oxidative stress and to perturb intracellular phosphorylation/dephosphorylation pathways. 25 In a study of ferret erythrocytes, Flatman and Creanor demonstrated that treatment of these cells with arsenite resulted in the stimulation of an ion transporter, the Na ϩ K ϩ 2Cl Ϫ cotransporter. 26 In this work, we investigated the effect of arsenite treatment on the transport into human erythrocytes of the acidic amino acid, glutamate. Human erythrocytes have a low basal permeability to glutamate; however, the amino acid readily enters P falciparum-infected erythrocytes. 1,2,27,28 Here we show that arsenite-treatment of (uninfected) human erythrocytes results in the activation of a high-affinity, Na ϩ -dependent glutamate transport pathway, which has the functional characteristics of members of the "excitatory amino acid transporter" (EAAT) family. 29,30 An analysis of the uptake of glutamate into P falciparum-infected ...

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Characterization of permeation pathways appearing in the host membrane of Plasmodium falciparum infected red blood cells

Cited by 200 publications

References 16 publications

Specific Inhibition of the Plasmodial Surface Anion Channel by Dantrolene

Specific Inhibition of the Plasmodial Surface Anion Channel by Dantrolene

A Malaria Parasite-encoded Vacuolar H+-ATPase Is Targeted to the Host Erythrocyte

Chemical activation of a high-affinity glutamate transporter in human erythrocytes and its implications for malaria-parasite–induced glutamate uptake

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