Abstract
The malaria parasite Plasmodium falciparum is exposed, during its development, to major changes of ionic composition in its surrounding medium. We demonstrate that the P. falciparum serpentine-like receptor PfSR25 is a monovalent cation sensor capable of modulating Ca2+ signaling in the parasites. Changing from high (140 mM) to low (5.4 mM) KCl concentration triggers [Ca2+]cyt increase in isolated parasites and this Ca2+ rise is blocked either by phospholipase C (PLC) inhibition or by depleting the parasite’s internal Ca2+ pools. This response persists even in the absence of free extracellular Ca2+ and cannot be elicited by addition of Na+, Mg2+ or Ca2+. However, when the PfSR25 gene was deleted, no effect on [Ca2+]cyt was observed in response to changing KCl concentration in the knocked out (PfSR25−) parasite. Finally, we also demonstrate that: i) PfSR25 plays a role in parasite volume regulation, as hyperosmotic stress induces a significant decrease in parasite volume in wild type (wt), but not in PfSR25− parasites; ii) parasites lacking PfSR25 show decreased parasitemia and metacaspase gene expression on exposure to the nitric oxide donor sodium nitroprusside (SNP) and iii), compared to PfSR25− parasites, wt parasites showed a better survival in albumax-deprived condition.
Highlights
Malaria is responsible for 2–3 million deaths annually[1, 2]
We demonstrate that PfSR25 (PlasmoDB number PF3D7_0713400), a member of a family of putative G protein-coupled receptors (GPCRs), which includes PfSR1, PfSR10, PfSR12, and PfSR25 that were recently identified in Plasmodium database[8], couples changes in extra parasitic K+ levels to PLC activation and intracellular Ca2+ mobilization
Though searched intensively, proteins similar to mammalian GPCRs have been discovered in Plasmodia only very recently
Summary
Malaria is responsible for 2–3 million deaths annually[1, 2]. The etiological agent of the most aggressive form of the disease, Plasmodium falciparum, upon RBC invasion resides inside a vacuole and undergoes various developmental changes, through the stages R (Ring), T (Trophozoite) and S (Schizont). We have shown previously that the Plasmodium vacuolar membrane is endowed with the capacity to generate a microenvironment around the parasites[4] with a sufficient Ca2+ concentration to allow Ca2+ signaling to persist in the intracellular stage[5]. Exposure of liver-cell invading P. berghei parasites to high K+ stimulates cell invasion by the rodent malaria sporozoite[6]; along the same line, reducing K+ from 140 mM to 5 mM K+ in P. falciparum merozoites causes a rise in [Ca2+]cyt, leading to microneme secretion and merozoite egress from RBCs7. We hereby demonstrate that PfSR25− parasites are more susceptible to stress induced by NO production compared to wt cells, with a much larger increase in metacaspase expression. We observed that PfSR25− parasites show higher inhibition in hemozoin formation after piperaquine treatment in comparison to wt parasites
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