Identification of Intracellular and Plasma Membrane Calcium Channel Homologues in Pathogenic Parasites

Abstract

Ca2+ channels regulate many crucial processes within cells and their abnormal activity can be damaging to cell survival, suggesting that they might represent attractive therapeutic targets in pathogenic organisms. Parasitic diseases such as malaria, leishmaniasis, trypanosomiasis and schistosomiasis are responsible for millions of deaths each year worldwide. The genomes of many pathogenic parasites have recently been sequenced, opening the way for rational design of targeted therapies. We analyzed genomes of pathogenic protozoan parasites as well as the genome of Schistosoma mansoni, and show the existence within them of genes encoding homologues of mammalian intracellular Ca2+ release channels: inositol 1,4,5-trisphosphate receptors (IP3Rs), ryanodine receptors (RyRs), two-pore Ca2+ channels (TPCs) and intracellular transient receptor potential (Trp) channels. The genomes of Trypanosoma, Leishmania and S. mansoni parasites encode IP3R/RyR and Trp channel homologues, and that of S. mansoni additionally encodes a TPC homologue. In contrast, apicomplexan parasites lack genes encoding IP3R/RyR homologues and possess only genes encoding TPC and Trp channel homologues (Toxoplasma gondii) or Trp channel homologues alone. The genomes of parasites also encode homologues of mammalian Ca2+ influx channels, including voltage-gated Ca2+ channels and plasma membrane Trp channels. The genome of S. mansoni also encodes Orai Ca2+ channel and STIM Ca2+ sensor homologues, suggesting that store-operated Ca2+ entry may occur in this parasite. Many anti-parasitic agents alter parasite Ca2+ homeostasis and some are known modulators of mammalian Ca2+ channels, suggesting that parasite Ca2+ channel homologues might be the targets of some current anti-parasitic drugs. Differences between human and parasite Ca2+ channels suggest that pathogen-specific targeting of these channels may be an attractive therapeutic prospect.

Ca2+ signalling early in evolution – all but primitive

“…Only in D. discoideum has a molecule with overall similarity, but without confirmed CRC role, been reported (Traynor et al, 2000). Even more uncertain in unicellular organisms is the existence of RyRs, because they are generally assumed to be absent from protozoa (Prole and Taylor, 2011) and algae (Verret et al, 2010). For a number of unicellular organisms, database searches reveal partial sequences with some -although variable -similarity to the InsP 3 R (Fig.…”

Inseparable tandem: evolution chooses ATP and Ca2+to control life, death and cellular signalling

“…In evolution, TPCs are present in monokonts, from choanoflagellates and the social amoeba Dictyostelium [105]) to mammals [100], and in bikonts, from protozoa to green plants [101,106]. In plants, TPCs can be activated by osmotic stress [107] as well as by Ca 2þ ions (this Ca 2þ -dependent activation contributes to regulation of seed germination and stomatal movement [108]).…”

“…In the parasitic monokont, Trypanosoma, NAADP does not trigger Ca 2þ response in contrast to the bikont apicomplexan parasite Toxoplasma gondii, a relative of ciliates [110]. The T. gondii also possesses a plant-like vacuole and acidocalcisomes, which may bear TPC channels encoded by orthologous genes that are absent in Apicomplexa [106].…”

“…In protozoa, systematic analysis is scant and assignment to eukaryotic, specifically mammalian types is difficult. For the bikont Paramecium, originally no TRP channel genes had been found [106], but then three genes were retrieved [121]. Parasitic relatives of Paramecium, Apicomplexa, Toxoplasma gondii and probably also Plasmodium spp.…”

“…Parasitic relatives of Paramecium, Apicomplexa, Toxoplasma gondii and probably also Plasmodium spp. all possess genes encoding TRP channels [106]. Parasitic flagellates Leishmania and Trypanosoma also possess TRP channel, but for all unicellular parasites, molecular characterization is yet to be done [110].…”