The calcium connection

Credit: V. BRINKMANN/ELSEVIER

One of the most visually striking events in the life cycle of the malaria parasite is exflagellation — the process by which the male reproductive cells emerge, complete with propellers, from a precursor cell. As they describe in Cell (117, 503–514; 2004), Oliver Billker and colleagues have pinned down the initial steps in the underlying cascade of molecular events.

The malaria parasite leads a complex life, relying on two hosts: humans and mosquitoes. It reproduces sexually in the insects. When a mosquito bites an infected human, it takes up red blood cells containing parasite gametocytes — pre-reproductive cells. Within seconds of being ingested, the gametocytes break out of their unwitting host cells, destroying them in the process. The resulting female reproductive cells (gametes) can be fertilized immediately, but the male cells must go through several more stages of development before fully fledged male gametes are formed.

Like all good parasites, the malaria agent takes advantage of its host's own machinery to spark off these events — the mosquito molecule xanthurenic acid acts as the trigger. But what happens next? Billker et al. chose to investigate the role of Ca²⁺ ions, common molecular mediators in many organisms, and Ca²⁺-binding proteins, of which there are many encoded in the parasite genome. To do so, the authors engineered Plasmodium berghei — a rodent malaria parasite — to carry a molecule that glows brightly in the presence of Ca²⁺ ions. When they added xanthurenic acid to mouse blood containing these engineered parasites, the gametocytes lit up (the Ca²⁺ detected probably coming from stores within the parasites).

So what occurs downstream of the release of Ca²⁺ ions in the production of gametes? Billker et al. wondered if a protein of the calcium-dependent protein kinase (CDPK) family might be implicated. Indeed, the authors found that one member of the family, CDPK4, is expressed predominantly in male P. berghei gametocytes. They then went on to generate parasites lacking this protein. As the top two images show, mutant male gametocytes were able to emerge successfully from red blood cells (left, red blood cells; right, a rounded male gametocyte emerging from the ghost of its host). But they could not exflagellate: to do so, CDPK4 had to be reinstated (see the lower two images; an exflagellating gametocyte, with protruding propellers, is on the right).

It remains to be seen what comes next in this game of molecular dominoes. Billker et al. also want to know where exactly the Ca²⁺ ions are stored inside gametocytes — and is there a counterpart of CDPK4 in the female cells?