The calcium signaling toolkit of the Apicomplexan parasites Toxoplasma gondii and Plasmodium spp

Abstract

Apicomplexan parasites have complex life cycles, frequently split between different hosts and reliant on rapid responses as the parasites react to changing environmental conditions. Calcium ion (Ca(2+)) signaling is consequently essential for the cellular and developmental changes that support Apicomplexan parasitism. Apicomplexan genomes reveal a rich repertoire of genes involved in calcium signaling, although many of the genes responsible for observed physiological changes remain unknown. There is evidence, for example, for the presence of a nifedipine-sensitive calcium entry mechanism in Toxoplasma, but the molecular components involved in Ca(2+) entry in both Toxoplasma and Plasmodium, have not been identified. The major calcium stores are the endoplasmic reticulum (ER), the acidocalcisomes, and the plant-like vacuole in Toxoplasma, or the food vacuole in Plasmodium spp. Pharmacological evidence suggests that Ca(2+) release from intracellular stores may be mediated by inositol 1,4,5-trisphosphate (IP3) or cyclic ADP ribose (cADPR) although there is no molecular evidence for the presence of receptors for these second messengers in the parasites. Several Ca(2+)-ATPases are present in Apicomplexans and a putative mitochondrial Ca(2+)/H(+) exchanger has been identified. Apicomplexan genomes contain numerous genes encoding Ca(2+)-binding proteins, with the notable expansion of calcium-dependent protein kinases (CDPKs), whose study has revealed roles in gliding motility, microneme secretion, host cell invasion and egress, and parasite differentiation. Microneme secretion has also been shown to depend on the C2 domain containing protein DOC2 in both Plasmodium spp. and Toxoplasma, providing further evidence for the complex transduction of Ca(2+) signals in these organisms. The characterization of these pathways could lead to the discovery of novel drug targets and to a better understanding of the role of Ca(2+) in these parasites.

Keywords: Acidic calcium; Acidocalcisome; Calcium; Calcium entry; Calcium-dependent protein kinases; Microneme; Plasmodium; Toxoplasma gondii.

Figure 1

Schematic representation of the distribution of Ca²⁺ in a T. gondii tachyzoite. Abbreviations: Ca²⁺ entry is probably through Ca²⁺ channels. Once inside the cells, Ca²⁺ can be translocated back to the extracellular environment, primarily by the action of a PMCA. In addition, Ca²⁺ will become sequestered by the ER by the action of the SERCA-Ca²⁺-ATPase, sequestered by the acidocalcisome or the plant-like vacuole by the action of a Ca²⁺-ATPase (TgA1). Ca²⁺ could also be released into the cytoplasm from internal stores as the ER through an uncharacterized channel by the action of IP₃ (generated from PIP₂ by a PLC) or cADP-ribose (generated from NAD⁺ by an ADP ribosyl cyclase). It may also be released from the PLV and the acidocalcisome through a Ca²⁺/H⁺ exchanger. CDPKs stimulate gliding motility and microneme secretion, which is also stimulated by DOC2.