Electrophysiological studies of malaria parasite-infected erythrocytes: Current status

Staines, Henry M.; Alkhalil, Abdulnaser; Allen, Richard J.; Jonge, Hugo R. de; Derbyshire, Elvira T.; Egée, Stéphane; Ginsburg, Hagaï; Hill, David R.C.; Huber, Stephan M.; Kirk, Kiaran; Läng, Florian; Lisk, Godfrey; Oteng, Eugene K.; Pillai, Ajay D.; Rayavara, Kempaiah; Rouhani, Sherin J.; Saliba, Kevin J.; Shen, Crystal; Solomon, Tsione; Thomas, Serge; Verloo, Patrick; Desai, Sanjay A.

doi:10.1016/j.ijpara.2006.12.013

Cited by 100 publications

(97 citation statements)

References 14 publications

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“…A clear understanding of the role of CLAG3 has been limited by the lack of homology to known ion channels and a relative paucity of hydrophobic regions for the formation of transmembrane domains. Additional complexities include the presence of multiple CLAG paralogs in P. falciparum (12) and the possibility that parasite proteins indirectly activate host erythrocyte channels (43).…”

Section: Discussionmentioning

confidence: 99%

A CLAG3 Mutation in an Amphipathic Transmembrane Domain Alters Malaria Parasite Nutrient Channels and Confers Leupeptin Resistance

et al. 2015

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Erythrocytes infected with malaria parasites have increased permeability to ions and nutrients, as mediated by the plasmodial surface anion channel (PSAC) and recently linked to parasite clag3 genes. Although the encoded protein is integral to the host membrane, its precise contribution to solute transport remains unclear because it lacks conventional transmembrane domains and does not have homology to ion channel proteins in other organisms. Here, we identified a probable CLAG3 transmembrane domain adjacent to a variant extracellular motif. Helical-wheel analysis revealed strict segregation of polar and hydrophobic residues to opposite faces of a predicted ␣-helical transmembrane domain, suggesting that the domain lines a water-filled pore. A single CLAG3 mutation (A1210T) in a leupeptin-resistant PSAC mutant falls within this transmembrane domain and may affect pore structure. Allelic-exchange transfection and site-directed mutagenesis revealed that this mutation alters solute selectivity in the channel. The A1210T mutation also reduces the blocking affinity of PSAC inhibitors that bind on opposite channel faces, consistent with global changes in channel structure. Transfected parasites carrying this mutation survived a leupeptin challenge significantly better than a transfection control did. Thus, the A1210T mutation contributes directly to both altered PSAC activity and leupeptin resistance. These findings reveal the molecular basis of a novel antimalarial drug resistance mechanism, provide a framework for determining the channel's composition and structure, and should guide the development of therapies targeting the PSAC.T he human malaria parasite Plasmodium falciparum remodels its host erythrocyte by exporting many proteins, generating membranous structures in the host cytosol, and increasing erythrocyte permeability to many solutes. Studies by multiple groups have determined that anions, sugars, purines, organic cations, and some vitamins have increased permeability after infection (1-4). The increase in permeability is primarily mediated by a parasitederived ion and nutrient channel known as the plasmodial surface anion channel (PSAC) (5). Importantly, both PSAC single-channel properties and the relative increases in solute permeabilities are conserved in divergent malaria parasites (6). Because Babesia parasites do not induce PSAC-like activity in erythrocytes that they invade (7), this channel is thought to be restricted to the genus Plasmodium.The clag multigene family, also conserved in and restricted to malaria parasites (8), has recently been linked to PSAC activity (9-11). Two paralogs on parasite chromosome 3, known as clag3.1 and clag3.2, appear to play a critical role, as identified by genetic mapping experiments with ISPA-28, an isolate-specific PSAC antagonist that blocks channels on the Dd2 laboratory clone but is ineffective against channels from other lines. These genes undergo epigenetic switching to encode a single protein that is initially packaged in specialized organelles known as rh...

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Section: Discussionmentioning

confidence: 99%

A CLAG3 Mutation in an Amphipathic Transmembrane Domain Alters Malaria Parasite Nutrient Channels and Confers Leupeptin Resistance

et al. 2015

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Section: The Uptake Of L-glutamate Into P Falciparum-infected Human Ementioning

confidence: 62%

“…This pathway may be equated with the broad-specificity anion-selective channels induced by the parasite in the host cell membrane. 45 However, as is also clear from Figure 4B and C, there is in addition to the low-affinity uptake component, one or more high-affinity components to the uptake of L-glutamate.A significant part of the high-affinity uptake of L-glutamate by P falciparum-infected human erythrocytes was Na ϩ -dependent; the magnitude of the saturable component of L-glutamate uptake was greater in cells suspended in Na ϩ -containing medium than in cells suspended in a medium in which Na ϩ was replaced with choline. This raises the possibility that the Na ϩ -glutamate transporter responsible for the uptake of L-glutamate into arsenitetreated erythrocytes is also active in the infected cells, providing a route for the high-affinity uptake of L-glutamate into the infected cell.…”

mentioning

confidence: 62%

“…1,27,28 Much of the parasite-induced transport has been attributed to the presence in the parasitized erythrocyte membrane of broad-specificity (and low-affinity) anion-selective channels. 3,16,18,44,45 A recent study provided evidence for the involvement of 2 parasite-encoded proteins in the formation of parasiteinduced channels, 24 and another proposed the involvement of an endogenous erythrocyte benzodiazopene receptor/voltagedependent anion channel. 20 As is clear from the data of Figure 4, the majority of the L-glutamate influx into P falciparum-infected human erythrocytes was via a low-affinity, Na ϩ -independent and furosemide-sensitive pathway.…”

Section: The Uptake Of L-glutamate Into P Falciparum-infected Human Ementioning

confidence: 99%

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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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“…Major changes that occur in the infected erythrocyte include the formation of small protrusions on the surface of the cell (knobs), alterations in ion channel behaviour (Decherf et al 2004;Staines et al 2007), the formation of novel channels for nutrient import (Saliba et al 1998;Desai et al 2000;Staines et al 2004), membrane rigidity and cell deformability (Glenister et al 2002) and altered behaviour of infected erythrocytes in the microcirculation (DiezSilva et al 2012). These modifications occur as a result of the export of various effector proteins in the infected erythrocyte.…”

Section: H O S T -C E L L M O D I F I C At I O N a N D P R O T E I N mentioning

confidence: 99%

Protein trafficking in Plasmodium falciparum-infected red cells and impact of the expansion of exported protein families

2014

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S U M M A R YErythrocytes are extensively remodelled by the malaria parasite following invasion of the cell. Plasmodium falciparum encodes numerous virulence-associated and host-cell remodelling proteins that are trafficked to the cytoplasm, the cell membrane and the surface of the infected erythrocyte. The export of soluble proteins relies on a sequence directing entry into the secretory pathways in addition to an export signal. The export signal consisting of five amino acids is termed the Plasmodium export element (PEXEL) or the vacuole transport signal (VTS). Genome mining studies have revealed that PEXEL/VTS carrying protein families have expanded dramatically in P. falciparum compared with other malaria parasite species, possibly due to lineage-specific expansion linked to the unique requirements of P. falciparum for host-cell remodelling. The functional characterization of such genes and gene families may reveal potential drug targets that could inhibit protein trafficking in infected erythrocytes. This review highlights some of the recent advances and key knowledge gaps in protein trafficking pathways in P. falciparum-infected red cells and speculates on the impact of exported gene families in the trafficking pathway.

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Electrophysiological studies of malaria parasite-infected erythrocytes: Current status

Cited by 100 publications

References 14 publications

A CLAG3 Mutation in an Amphipathic Transmembrane Domain Alters Malaria Parasite Nutrient Channels and Confers Leupeptin Resistance

A CLAG3 Mutation in an Amphipathic Transmembrane Domain Alters Malaria Parasite Nutrient Channels and Confers Leupeptin Resistance

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

Protein trafficking in Plasmodium falciparum-infected red cells and impact of the expansion of exported protein families

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