Plasmodium falciparum likely encodes the principal anion channel on infected human erythrocytes

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

doi:10.1182/blood-2004-05-2047

Cited by 84 publications

(153 citation statements)

References 30 publications

(49 reference statements)

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“…The IRC has some similarities to PSAC in that it exhibits fewer and shorter openings at positive Vm and flickering gating but with an Ϸ5-fold-higher single-channel conductance. It also shows significant differences in levels of inhibition by certain antagonists (NPPB and furosemide) and can be induced on uninfected erythrocytes by either membrane stretch or protein kinases, whereas Desai and colleagues (12) failed to activate channels by PKA and ATP on uninfected erythrocytes under their experimental conditions. The SCC also exhibits fewer and shorter openings at positive Vm and has a single-channel conductance close to the value calculated for PSAC at physiological ion concentrations but displays different gating.…”

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confidence: 99%

“…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 physiological ion concentration to 3 pS.…”

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confidence: 99%

“…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).To explore to what extent technical issues might account for the disparities in the reported electrophysiological data, we designed this series of experiments to follow the behavior of global membrane conductance and single-channel activity of infected RBCs exposed to increasing chloride concentrations from 115 mM (close to physiological conditions) to 1,150 mM [Desai's group (6,11,12)] and varied concentrations of the main inhibitors used by all groups. …”

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confidence: 99%

“…To explore to what extent technical issues might account for the disparities in the reported electrophysiological data, we designed this series of experiments to follow the behavior of global membrane conductance and single-channel activity of infected RBCs exposed to increasing chloride concentrations from 115 mM (close to physiological conditions) to 1,150 mM [Desai's group (6,11,12)] and varied concentrations of the main inhibitors used by all groups.…”

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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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confidence: 99%

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confidence: 99%

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confidence: 99%

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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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“…The molecular identity of the channel remains a mystery and there is some controversy as to whether and if the channel is composed of proteins derived from the parasite or simply remodeled from host proteins (Kirk, 2000). But despite this uncertainty there is a clear recognition that the channel is an attractive target for new drug design (Alkhalil, et al, 2004,Desai, 2004,Ginsburg and Stein, 2005,Kirk, 2004,Lisk, et al, 2006. It is hoped that the results reported here will aid in the effort to develop pharmacologic means to block or subvert the channel, leading to discovery of novel antimalarial agents.…”

Section: Discussionmentioning

confidence: 99%

Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye

Kelly

Winter

Braun³

et al. 2007

Experimental Parasitology

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Malaria is an infectious disease caused by protozoan parasites of the genus Plasmodium. The most virulent form of the disease is caused by P. falciparum which infects hundreds of millions of people and is responsible for the deaths of 1 to 2 million individuals each year. An essential part of the parasitic process is the remodeling of the red blood cell membrane and its protein constituents to permit a higher flux of nutrients and waste products into or away from the intracellular parasite. Much of this increased permeability is due to a single type of broad specificity channel variously called the new permeation pathway (NPP), the nutrient channel, and the Plasmodial surface anion channel (PSAC). This channel is permeable to a range of low molecular weight solutes both charged and uncharged, with a strong preference for anions. Drugs such as furosemide that are known to block anion-selective channels inhibit PSAC. In this study we have investigated a dye known as benzothiocarboxypurine, BCP, which had been studied as a possible diagnostic aid given its selective uptake by P. falciparum infected red cells. We found that the dye enters parasitized red cells via the furosemide-inhibitable PSAC, forms a brightly fluorescent complex with parasite nucleic acids, and is selectively toxic to infected cells. Our study describes an antimalarial agent that exploits the altered permeability of Plasmodium-infected red cells as a means to killing the parasite and highlights a chemical reagent that may prove useful in high throughput screening of compounds for inhibitors of the channel.

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Antimalarials

Smithson¹,

Guiguemde²,

Guy³

2010

Burger's Medicinal Chemistry and Drug Discovery

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While the treatment of malaria has until recently relied upon a small number of therapeutic agents with a few mechanisms of action, the past decade has seen a huge growth in the number of targets being addressed and new agents being pushed to the clinic. This chapter briefly reviews existing agents and close homologs in development and then carefully explores new targets and new chemotypes being developed.

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Plasmodium falciparum likely encodes the principal anion channel on infected human erythrocytes

Cited by 84 publications

References 30 publications

Toward a unifying model of malaria-induced channel activity

Toward a unifying model of malaria-induced channel activity

Selective killing of the human malaria parasite Plasmodium falciparum by a benzylthiazolium dye

Antimalarials

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