Calcium in the Backstage of Malaria Parasite Biology

Abstract

The calcium ion (Ca2+) is a ubiquitous second messenger involved in key biological processes in prokaryotes and eukaryotes. In Plasmodium species, Ca2+ signaling plays a central role in the parasite life cycle. It has been associated with parasite development, fertilization, locomotion, and host cell infection. Despite the lack of a canonical inositol-1,4,5-triphosphate receptor gene in the Plasmodium genome, pharmacological evidence indicates that inositol-1,4,5-triphosphate triggers Ca2+ mobilization from the endoplasmic reticulum. Other structures such as acidocalcisomes, food vacuole and mitochondria are proposed to act as supplementary intracellular Ca2+ reservoirs. Several Ca2+-binding proteins (CaBPs) trigger downstream signaling. Other proteins with no EF-hand motifs, but apparently involved with CaBPs, are depicted as playing an important role in the erythrocyte invasion and egress. It is also proposed that a cross-talk among kinases, which are not members of the family of Ca2+-dependent protein kinases, such as protein kinases G, A and B, play additional roles mediated indirectly by Ca2+ regulation. This statement may be extended for proteins directly related to invasion or egress, such as SUB1, ERC, IMC1I, IMC1g, GAP45 and EBA175. In this review, we update our understanding of aspects of Ca2+-mediated signaling correlated to the developmental stages of the malaria parasite life cycle.

Synthesis, Structure–Activity Relationships, and Parasitological Profiling of Brussonol Derivatives as New Plasmodium falciparum Inhibitors

“…CPA is a PfSERCA-specific inhibitor that modulates the cytosolic Ca 2+ homeostasis. In Plasmodium species, Ca 2+ signaling plays a central role in the parasite life cycle [ 38 , 51 ], including intraerythrocytic parasite proliferation invasion and egress from the host cell, protein secretion, and cell cycle regulation. The endoplasmic reticulum (ER) is the major intracellular Ca 2+ storage compartment in P. falciparum [ 51 ] and regulates cytosolic Ca 2+ through the sarco/endoplasmic reticulum Ca 2+ -ATPase (PfSERCA or PfATP6) pump.…”

“…In Plasmodium species, Ca 2+ signaling plays a central role in the parasite life cycle [ 38 , 51 ], including intraerythrocytic parasite proliferation invasion and egress from the host cell, protein secretion, and cell cycle regulation. The endoplasmic reticulum (ER) is the major intracellular Ca 2+ storage compartment in P. falciparum [ 51 ] and regulates cytosolic Ca 2+ through the sarco/endoplasmic reticulum Ca 2+ -ATPase (PfSERCA or PfATP6) pump. The addition of 10 μM brussonol in Fluo-4AM-loaded parasites elicited a sustained [Ca 2+ ] cyt rise, which increased steadily even after SERCA was inhibited by CPA.…”

“…These findings are in contrast with that observed with artemisinin derivatives, which act on the ER calcium store [ 52 , 53 , 54 , 55 ]. This [Ca 2 + ] cyt rise elicited by brussonol may originate from the extracellular media via Ca 2 + influx through membrane calcium channels or other intracellular calcium stores in Plasmodium, including mitochondria or acidic organelles [ 51 ]. In sum, although the brussonol target remains unknown, it did interfere with the Ca 2+ levels within the parasite, which is an interesting result that could explain the additive effect in the inhibitory activity when brussonol was combined with artesunate.…”

Bazedoxifene, a Postmenopausal Drug, Acts as an Antimalarial and Inhibits Hemozoin Formation

“…The antifungal activity of some SERMs has been shown to be through calmodulin inhibition ( 12 , 41 ). As calmodulin inhibition primarily affects invasion of erythrocytes by merozoites ( 42 – 44 ) and bazedoxifene had no effect on invasion of erythrocytes by merozoites, calmodulin inhibition is unlikely to be the mechanism of the antimalarial activity of bazedoxifene. Notably, a significant number of trophozoites developed from the parasites treated at early ring stage (0 h) did not contain hemozoin in the food vacuole ( Fig.…”

Updated List of Transport Proteins in Plasmodium falciparum

“…While many transporters were shown to reside in the acidocalcisome membrane in Trypanosoma brucei through proteomic studies and microscopy (Huang et al, 2014), no protein has been definitely localised to these organelles in P. falciparum (Magowan et al, 1997;Ruiz et al, 2004). Their low internal pH is likely required for the secondary active import of various ions and thought to be established and maintained by the plant-like H + -pump V-ATPase (Wunderlich et al, 2012;de Oliveira et al, 2021). This has yet to be verified experimentally, and there may be differences between parasite species.…”