The IP₃ receptor and Ca²⁺ signaling in trypanosomes

Trypanosoma cruzi, and the T. brucei group of parasites cause neglected diseases that affect millions of people around the world. These unicellular microorganisms have complex life cycles involving an insect vector and a mammalian host. Both groups of pathogens possess an inositol 1,4,5-trisphosphate (IP₃)/diacylglycerol (DAG) signaling pathway, and an IP₃ receptor, but with lineage-specific adaptations that make them different from their mammalian counterparts. The phospholipase C (PLC), which hydrolyzes phosphatidyl inositol 4,5-bisphosphate (PIP₂) to IP₃ is N-terminally myristoylated and palmitoylated. Acidocalcisomes, which are lysosome-related organelles rich in polyphosphate, are the main intracellular Ca²⁺ stores. The inositol 1,4,5-trisphosphate receptor (IP₃R) localizes to acidocalcisomes instead of the endoplasmic reticulum. The trypanosome IP₃R is stimulated by luminal phosphate and pyrophosphate, which are hydrolysis products of polyphosphate (polyP), and inhibited by tripolyphosphate (polyP₃), which is the most abundant polyP in acidocalcisomes. Ca²⁺ signaling is important for host cell invasion and differentiation and to maintain cellular bioenergetics.