Calcium Regulation and Signaling in Apicomplexan Parasites

Abstract

A picomplexan parasites rely on calcium-mediated signaling for a variety of vital functions including protein secretion, motility, cell invasion, and differentiation. These functions are controlled by a variety of specialized systems for uptake and release of calcium, which acts as a second messenger, and on the functions of calcium-dependent pro› teins. Defining these systems in parasites has been complicated by their evolutionary dis› tance from model organisms and practical concerns in working with small, and somewhat fastidious cells. Comparative genomic analyses of Toxoplasma gondii, Plasmodium spp. and Cryptosporidium spp. reveal several interesting adaptations for calcium-related processes in parasites. Apicomplexans contain several P-type Ca ^ ATPases including an ER-type reuptake mechanism (SERCA), which is the proposed target of artemisinin. All three organisms also contain several genes related to Golgi PMR-like calcium transporters, and a Ca^VH^ ex› changer, while plasma membrane-type (PMCA) Ca'^^ ATPases and voltage-dependent cal› cium channels are exclusively found in T gondii. Pharmacological evidence supports the presence of IP3 and ryanodine channels for calcium-mediated release. Collectively these sys› tems regulate calcium homeostasis and release calcium to act as a signal. Downstream re› sponses are controlled by a family of EF-hand containing calcium binding proteins includ› ing calmodulin, and an array of centrin and caltractin-like genes. Most surprising, apicomplexans contain a diversity of calcium-dependent protein kinases (CDPK), which are commonly found in plants. Toxoplasma contains more than 20 CDPK or CDPK-like pro› teases, while Plasmodium and Cryptosporidium have fewer than half this number. Several of these CDPKs have been shown to play vital roles in protein secretion, invasion, and differen› tiation, indicating that disruption of calcium-regulated pathways may provide a novel means for selective inhibition of parasites. Defining Calcium Regulation in an Early Branching EukaryoteApicomplexan parasites are most similar to ciliates and dinoflagellates and only distandy related to plants, fungi, and animals typically used as model organisms. Apicomplexans con› tain a remnant plastid derived from a secondary endosymbiont, called the apicoplast. A num› ber of plant-like metabolic systems are found in apicomplexans either due to retention of *Corresponding

Functional Dissection of Toxoplasma gondii Perforin-like Protein 1 Reveals a Dual Domain Mode of Membrane Binding for Cytolysis and Parasite Egress

“…PLP1 is a lytic protein with a unique postreplicative function in niche escape rather than a prereplicative function to access a replication site as seen for the pore-forming proteins of the aforementioned pathogens. This and other studies (21)(22)(23) support an emerging hypothesis of egress as an event the parasite actively regulates instead of a strictly passive process occurring upon exceeding a critical capacity. PLP1-deficient parasites failed to egress rapidly from the parasitophorous vacuole after calcium ionophore treatment, which induces microneme secretion and motility (24,25).…”

A novel Plasmodium-specific prodomain fold regulates the malaria drug target SUB1 subtilase

“…Calcium ions are ubiquitous and versatile signalling molecules that play pleiotropic roles in the complex cellular organization and life cycle [38][39][40][41][42] , including during the egress from and the subsequent invasion of host cells by Apicomplexan parasites 25,[43][44][45] . The secretion route of eukaryotic cells has a gradient of Ca 2 þ concentration ([Ca 2 þ ]), being high in the ER (up to 400 mM), decreasing through the Golgi apparatus (250-130 mM) to reach values lower than 100 mM within secretory vesicles 38 .…”

Ca2+ signalling early in evolution – all but primitive

“…Toxoplasma possess subplasmalemmal sacs, called the inner membrane complex that resembles alveolar sacs of ciliates -one of many reasons to combine both groups in the supergroup Alveolata. Apicomplexa require Ca 2+ signalling for sequential exocytosis of special densecore secretory vesicles (comparable with trichocysts in P. tetraurelia), which is a prerequisite for host cell penetration (Lovett and Sibley, 2003;Nagamune et al, 2008). Nevertheless, despite extensive searches, there is no indication for the existence of comparable CRCs in Apicomplexa (Nagamune and Sibley, 2006;Nagamune et al, 2008;Prole and Taylor, 2011;Plattner et al, 2012).…”

“…Apicomplexa require Ca 2+ signalling for sequential exocytosis of special densecore secretory vesicles (comparable with trichocysts in P. tetraurelia), which is a prerequisite for host cell penetration (Lovett and Sibley, 2003;Nagamune et al, 2008). Nevertheless, despite extensive searches, there is no indication for the existence of comparable CRCs in Apicomplexa (Nagamune and Sibley, 2006;Nagamune et al, 2008;Prole and Taylor, 2011;Plattner et al, 2012). Both, ascomycetes and apicomplexans are known for the secondary reduction of their genomes (Aravind et al, 2003;Roos, 2005), and they might have developed other sources of Ca 2+ and other types of CRC.…”