Toxoplasma need a plasma membrane ion exchanger (right) for a speedy exit.

The protozoan parasite Toxoplasma gondii heads out of its host cell when Ca2+ levels peak in its cytoplasm. Now, Arrizabalaga et al. (page 653) find that proper regulation of these Ca2+ levels, and thus of Toxoplasma exit, requires a Na+/H+ exchanger (NHE), suggesting a link between proton and Ca2+ regulation.

The increase in Ca2+ levels, which can be induced artificially with an ionophore, triggers a series of morphological changes that primes Toxoplasma for both exit and a speedy entrance into a neighboring cell. Death can ensue, however, if the ionophore sticks around while there is no target cell for the parasite to enter; presumably the overstimulated Toxoplasma cannot sustain itself in an activated state.

The authors used this death assay to isolate a mutant defective in activation. One mutant with a disruption in a sodium/hydrogen exchanger (NHE) showed both delayed exit and reduced Toxoplasma cell death after sustained ionophore exposure. Toxoplasma lacking this plasma membrane pump also had normal internal pH, but their proton efflux was no longer prevented with an NHE inhibitor.

Resting Ca2+ levels were higher in mutant parasites. This would make it harder to detect any exit signal that increased these Ca2+ levels even further, perhaps explaining why these mutants are slow to exit. The increase in resting Ca2+ levels may come about if a Ca2+ exporter (Ca2+ out/H+ in) relies on prior action of the NHE (H+ out/Na+ in). Such a hypothetical linkage may be part of regulating Toxoplasma mobility or simply an intersection between the exit system and Toxoplasma's normal ion homeostasis. ▪