Plasmodium falciparum, the etiological agent of the human malaria parasite is exposed to large shifts in K+ concentration during its life cycle. Unraveling the signaling pathways that allow normal parasite growth in diverse ionic environments is fundamental for a better understanding of the disease that affects roughly 500 million people each year. We have demonstrated that the P. falciparum GPCR-like receptor PfSR25 is a monovalent cation sensor and capable of modulating Ca2+ signaling in parasites. Immunofluorescence analysis reveals that PfSR25 is expressed throughout the P. falciparum RBC cycle.
KCl stimulates cytosolic calcium ([Ca2+]cyt) increase in isolated parasites.at Red Blood Cells cycle. The Ca2+ rise is blocked either by PLC inhibition or by depleting the parasite’s internal Ca2+ pools but remains in the absence of free extracellular calcium and cannot be elicited by addition of Na+, Mg2+ or Ca2+. Similar assays performed with PfSR25 knockout parasites (PfSR25-) had no effect on [Ca2+]cyt in response to change in KCl, thus confirming the relevance of the receptor in the KCl/Ca2+ signaling.
We have also demonstrated that parasites lacking PfSR25 showed reduced parasitemia when exposed to nitric oxide donor sodium nitroprusside (SNP), antimalarial drug chloroquine and in albumax-deprived condition. In addition, the ability to polymerize the toxic heme into hemozoin is reduced after 2 hours of treatment with the antimalarial piperaquine. To our knowledge this is the first identification of a GPCR-like protein in the human malaria parasite.