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.

Keywords: Apicomplexan parasites; Calcium signaling; InsP3 signaling; Phosphoinositides; Plasmodium.

Fig. (1)

Schematic representation of the myo-inositol 1,4,5-triphosphate (InsP₃) turnover and its function in intracellular Ca²⁺ release. Step 1: Inositol incorporation into CDP-DAG (CDP = cytidine diphosphate DAG = diacylglycerol) catalyzed by phosphatidylinositol synthase generating phosphatidylinositol (PI). Step 2: Phosphorylation of PI by phosphatidylinositol 4-kinase forming phosphatidylinositol 4-phosphate (PIP). Step 3: Phosphorylation of PIP by phosphatidylinositol 4-phosphate 5-kinase forming phosphatidyl 4,5-bisphosphate (PIP₂). Step 4: PIP₂ is cleaved by phospholipase C (PLC) generating a soluble molecule, inositol 1,4,5-trisphosphate (InsP₃), that is capable to bind to a InsP₃ receptor (InsP₃R) present in the membranes of intracellular compartments. InsP₃ binding temporarily opens the InsP₃R that acts as a Ca²⁺-release channel, so that Ca²⁺ can flow into the cytoplasm. The insoluble fraction formed by cleavage of PIP₂ is diacylglycerol (DAG). Step 5: InsP₃ is dephosphorylated by inositolpolyphosphate 5-phosphatase forming inositol 1,4-bisphosphate (InsP₂). Step 6: InsP₂ is desphosphorylated by inositol polyphosphate 1-phosphatase generating inositol 1-monophosphate (InsP). Step 7: Dephosphorylation of InsP to inositol by inositol monophosphatase. Step 8: phosphorylation of InsP₃ by inositol 1,4,5-trisphosphate 3-kinase generating inositol 1,3,4,5-tetrakisphosphate (InsP₄).

Fig. (2)

Phylogenetic tree showing evolutionary relationships among organisms discussed in this review.