Calcium regulation in the intraerythrocytic malaria parasite Plasmodium falciparum

Alleva, Lisa M.; Kirk, Kiaran

doi:10.1016/s0166-6851(01)00338-3

Cited by 86 publications

(92 citation statements)

References 29 publications

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“…4C and 5B). These results help explain previous observations of transient elevations of Ca 2ϩ upon addition of cyclopiazonic acid (20). In addition these results suggest the operation of more than one P-type Ca 2ϩ ATPase, one that is sensitive to both thapsigargin and cyclopiazonic acid and one that is only sensitive to cyclopiazonic acid.…”

Section: Discussionsupporting

confidence: 88%

“…capacitative Ca 2ϩ entry (26). However, it is unlikely that capacitative Ca 2ϩ entry is responsible for the observed increase in cytoplasmic Ca 2ϩ on treatment with cyclopiazonic acid, as this effect was observed by Alleva and Kirk (20) to occur in freed P. falciparum parasites suspended in Ca 2ϩ -free solutions.…”

Section: Discussionmentioning

confidence: 85%

“…However, negative staining of the digestive vacuole by UV-excitable Ca 2ϩ fluorescent probes precluded its involvement (20). We have shown recently that FPIX can interact with fluorescent probes such as acridine orange, resulting in a dramatic reduction in fluorescent emission, probably occurring from the absorption by the FPIX Soret peak (21).…”

Section: Discussionmentioning

confidence: 99%

“…We have shown recently that FPIX can interact with fluorescent probes such as acridine orange, resulting in a dramatic reduction in fluorescent emission, probably occurring from the absorption by the FPIX Soret peak (21). We therefore investigated whether the fluorescent emission of previously used UV-excitable Ca 2ϩ -specific probes such as Fura2 (19,20) as well as a range of visible light-excitable Ca 2ϩ probes were also affected by FPIX. Titration of FPIX to solutions of Fura-2 or Fluo-4 resulted in a progressive reduction of fluorescence signal (Fig.…”

Section: Discussionmentioning

confidence: 99%

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The Digestive Food Vacuole of the Malaria Parasite Is a Dynamic Intracellular Ca2+ Store

Biagini

Bray

Spiller

et al. 2003

Journal of Biological Chemistry

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The acidic food vacuole of Plasmodium falciparum has been the subject of intense scientific investigation in the 40 years since its role in the digestion of host hemoglobin was first suggested. This proposed role has important implications for the complex host-parasite inter-relationship and also for the mode of action of several of the most effective antimalarial drugs. In addition, adaptive changes in the physiology of this organelle are implicated in drug resistance. Here we show that in addition to these functions, the digestive food vacuole of the malaria parasite is a dynamic internal store for free Ca 2؉ , a role hitherto unsuspected. With the aid of live-cell laser scanning confocal imaging, spatiotemporal studies revealed that maintenance of elevated free Ca 2؉ in the digestive food vacuole (relative to cytosolic levels) is achieved by a thapsigargin (and cyclopiazonic acid)-sensitive Ca 2؉ -pump in cooperation with a H ؉ -dependent Ca 2؉ transporter. Redistribution of free cytosolic and vacuolar Ca 2؉ during parasite growth also suggests that vacuolar Ca 2؉ plays an essential role in parasite morphogenesis. These data imply that the digestive food vacuole of the malaria parasite is functionally akin to the vacuole of plants (tonoplast) and the small electron-dense granules of some parasites (acidocalcisomes) whereby H ؉ -coupled Ca 2؉ transport is involved in ion transport, Ca 2؉ homeostasis, and signal transduction. These findings have significant implications for parasite development, antimalarial drug action, and mechanisms of drug resistance.Malaria remains one of the largest global health (and economic) problems, resulting in more than a million deaths, mostly in young African children (1). With this in mind, it is astonishing how little is known about the basic physiology of the intraerythrocytic malaria parasite and its organelles. The food vacuole is a major digestive organelle of the malaria parasite and a proven chemotherapeutic target. This organelle has a role in degradation of host-derived hemoglobin, is the site of action of important classes of antimalarials, and harbors transporters associated with drug resistance (2-4). Hydrolysis of hemoglobin in the malaria parasite digestive food vacuole occurs by the integrated action of aspartic, cysteine, and metalloproteases (5), resulting in the production of hemozoin (malaria pigment), a biocrystal of the toxic precursor ferriprotoporphyrin IX (FPIX) 1 (6). The internal pH of the digestive food vacuole is lower than the parasite cytosol, although the precise pH value is under debate (7). In collaboration with Prof. Kiaran Kirk's laboratory (8), we have recently described the function of two H ϩ -pumping mechanisms in the digestive food vacuole; one is a bafilomycin-sensitive V-type H ϩ -ATPase, and the other is a NaF-sensitive H ϩ -pyrophosphatase showing a partial dependence on K ϩ . The combination of a H ϩ -ATPase and a H ϩ -pyrophosphatase acting in the digestive vacuole is analogous to the situation in acidic tonoplasts of plant cells (9)...

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Digestive Food Vacuole of the Malaria Parasite Is a Dynamic Intracellular Ca2+ Store

Biagini

Bray

Spiller

et al. 2003

Journal of Biological Chemistry

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“…Saponin renders the erythrocyte and parasitophorous vacuole membranes permeable to macromolecules (Ansorge et al, 1996) but leaves the parasite plasma membrane intact and able to maintain transmembrane ion gradients (Saliba and Kirk, 1999;Alleva and Kirk, 2001) as well as a substantial membrane potential (Allen and Kirk, 2004). Following saponin treatment the isolated parasites were washed (>3×) and resuspended in a HEPESbuffered saline (125 mM NaCl, 5 mM KCl, 1 mM MgCl 2 , 20 mM glucose and 25 mM HEPES, pH 7.1).…”

Section: Parasite Preparationmentioning

confidence: 99%

Transport of nucleosides across the Plasmodium falciparum parasite plasma membrane has characteristics of PfENT1

Downie¹,

Saliba

Howitt³

et al. 2006

Molecular Microbiology

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SummaryLike all parasitic protozoa, the human malaria parasite Plasmodium falciparum lacks the enzymes required for de novo synthesis of purines and it is therefore reliant upon the salvage of these compounds from the external environment. P. falciparum equilibrative nucleoside transporter 1 (PfENT1) is a nucleoside transporter that has been localized to the plasma membrane of the intraerythrocytic form of the parasite. In this study we have characterized the transport of purine and pyrimidine nucleosides across the plasma membrane of 'isolated' trophozoite-stage P. falciparum parasites and compared the transport characteristics of the parasite with those of PfENT1 expressed in Xenopus oocytes. The transport of nucleosides into the parasite: (i) was, in the case of adenosine, inosine and thymidine, very fast, equilibrating within a few seconds; (ii) was of low affinity [ K m (adenosine) = 1.45 ± 0.25 mM; K m (thymidine) = 1.11 ± 0.09 mM]; and (iii) showed 'crosscompetition' for adenosine, inosine and thymidine, but not cytidine. The kinetic characteristics of nucleoside transport in intact parasites matched very closely those of PfENT1 expressed in Xenopus oocytes [ K m (adenosine) = 1.86 ± 0.28 mM; K m (thymidine) = 1.33 ± 0.17 mM]. Furthermore, PfENT1 transported adenosine, inosine and thymidine, with a cross-competition profile the same as that seen for isolated parasites. The data are consistent with PfENT1 serving as a major route for the uptake of nucleosides across the parasite plasma membrane.

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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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Calcium regulation in the intraerythrocytic malaria parasite Plasmodium falciparum

Cited by 86 publications

References 29 publications

The Digestive Food Vacuole of the Malaria Parasite Is a Dynamic Intracellular Ca2+ Store

The Digestive Food Vacuole of the Malaria Parasite Is a Dynamic Intracellular Ca2+ Store

Transport of nucleosides across the Plasmodium falciparum parasite plasma membrane has characteristics of PfENT1

Antimalarials

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