Calcium and cyclic nucleotide signaling networks in Toxoplasma gondii

Abstract

Apicomplexan parasites of medical or veterinary interest are obligate intracellular parasites that display actin-myosin powered motility, control the secretion of adhesive proteins, and actively penetrate their host cells. Following an intracellular replicative phase, they emerge from their spent host cell by a process of active egress. The transition between these two modes of active motility, required for invasion/egress, versus a nonmotile state required for intracellular replication must be balanced to respond to environmental clues and promote efficient growth. These processes are regulated by two interrelated signaling pathways that control intracellular calcium and cyclic nucleotides. In turn, these second messengers coordinate the action of calcium-dependent and nucleotide-dependent kinases that control motility, secretion, invasion, egress, and also balance the transition to the quiescent replicative phase of the life cycle. Genetic and chemical biology approaches have uncovered the intricate control of these pathways and documented the essentiality of many of their key components. For example, secretion of adhesive microneme proteins and activation of motility requires the activity of protein kinase (PK) G, as well as downstream calcium dependent kinases such as CDPK1. In contrast, activation of PK A dampens calcium signaling and leads to a quiescent intracellular replicative phase. These two nucleotide dependent kinases are governed by cyclic nucleotides, the levels of which are controlled by a family of cyclases and phosphodiesterase. In addition to elucidating the intricacies of biological control, these studies identify several essential and novel candidates for development of selective inhibitors that may be used to block infection.