InsP3 Signaling in Apicomplexan Parasites

Abstract

Background: Phosphoinositides (PIs) and their derivatives are essential cellular components that form the building blocks for cell membranes and regulate numerous cell functions. Specifically, the ability to generate myo-inositol 1,4,5-trisphosphate (InsP3) via phospholipase C (PLC) dependent hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to InsP3 and diacylglycerol (DAG) initiates intracellular calcium signaling events representing a fundamental signaling mechanism dependent on PIs. InsP3 produced by PI turnover as a second messenger causes intracellular calcium release, especially from endoplasmic reticulum, by binding to the InsP3 receptor (InsP3R). Various PIs and the enzymes, such as phosphatidylinositol synthase and phosphatidylinositol 4-kinase, necessary for their turnover have been characterized in Apicomplexa, a large phylum of mostly commensal organisms that also includes several clinically relevant parasites. However, InsP3Rs have not been identified in genomes of apicomplexans, despite evidence that these parasites produce InsP3 that mediates intracellular Ca2+ signaling.Conclusion: Evidence to supporting IP3-dependent signaling cascades in apicomplexans suggests that they may harbor a primitive or non-canonical InsP3R. Understanding these pathways may be informative about early branching eukaryotes, where such signaling pathways also diverge from animal systems, thus identifying potential novel and essential targets for therapeutic intervention.

Essential cGMP Signaling in Toxoplasma Is Initiated by a Hybrid P-Type ATPase-Guanylate Cyclase

“…Cytosolic Ca 2+ is kept at low levels by organelle sequestration during immotile replicative stages but elevated during processes such as egress, migration, and invasion (Lourido and Moreno, 2015). It has been proposed that IP 3 produced from phosphoinositide phospholipase C (PI-PLC) cleavage of PIP 2 opens an IP 3 -sensitive Ca 2+ channel (Lovett et al, 2002), though such channels have eluded identification in apicomplexans (Garcia et al, 2017). Once released, cytosolic Ca 2+ activates apicomplexan calcium dependent protein kinases (CDPKs) (Billker et al, 2009; Lourido et al, 2010) and vesicle trafficking (Farrell et al, 2012) to promote microneme secretion.…”

BRET sensors unravel thatPlasmodium falciparumserpentine receptor 12 (PfSR12) increases surface expression of mammalian GPCRs in HEK293 cells

“…Although a canonical PKC could not be found in P. falciparum genome, there is an active PLC that participates in cell signaling processes, as well as orphan kinases that could supply the PKC deficiency acting in a similar way (Alves et al 2011;Garcia et al 2017;Moraes et al 2017). Moreover, the parasite expresses a functional receptor for Kinase C (PfRACK) with conserved domains for PKC anchoring, which supports the possibility of another kinase playing the role of PKC (Madeira et al 2008;Sartorello et al 2009).…”

Evolutionary Cell Biology of Proteins from Protists to Humans and Plants

“…Currently, data are frequently retrieved solely by data mining, whereas only in few protozoa, some channels have been experimentally verified and, thus, made comparable to animals and plants. Many channels emerge early on in evolution; some, like IP 3 Rs, are maintained from ciliates, flagellates, and myxamoebae up to man (Plattner and Verkhratsky ), but up to now remained untraceable in plants (Edel and Kudla ) and apicomplexan parasites (Garcia et al …”