6.6 ION METABOLISM AND TRANSPORT

• The uptake of extracellular calcium (Ca⁺⁺) is essential for the growth of malaria parasites. The Ca⁺⁺ content of infected cells increases as the parasite matures and this is due to an increased permeability of infected cells to external Ca2+ (this permeability may be 20 times higher than in normal cells). The accumulated Ca⁺⁺ is exclusively localized in the parasite compartment. Since malaria-infected cells actively incorporate extracellular Ca⁺⁺, it is not surprising that blockers of Ca⁺⁺ channels (e.g. verapamil) or antagonists of calmodulin (e.g. diltiazem or calmidazolium) may arrest parasite development. These same molecules are capable of reversing chloroquine resistance in P. falciparum in vitro, suggestive of the presence in resistant parasites of an active drug efflux pump with similarities to the P-glycoprotein of multidrug resistant cancer cells (MDR). Resistant P. falciparum do possess such a molecule (Pf-MDR) and can rid themselves of chloroquine 40-50 fold faster than sensitive parasites.

• Malaria parasites, like most eukaryotic cells, are capable of maintaining a high level of K+ and a low level of Na+ in their cytoplasm by means of a Na+/K+/ATPase and at the expense of the host cell ionic environment. Interestingly, the ATPase has been identified in the parasitophorous vacuole membrane (not in the parasite membrane), which implies that the parasite is living in a low Na+, high K+ extracellular environment; this unusual feature is consistent with the observation that it is necessary to use a low Na+, high K+ medium in order to grow extracellular trophozoites of P. lophurae or P. falciparum.

• The requirement for iron in a number of metabolic pathways, including the synthesis of DNA, explains why the parasite may be inhibited by relatively low amounts of desferrioxamine. Although haemoglobin is degraded within its food vacuoles, most of the haem released is transformed into crystalline haemozoin ('malarial pigment') and does not represent a usable source of free iron. It has been suggested that extracellular iron may be taken up by the parasite either by the binding of ferrotransferrin (from serum transferrin) to a parasite transferrin receptor in the infected erythrocyte membrane, followed by the invagination of small vesicles, or by means of a transferrin-independent mechanism. The role of iron in the viability of malaria parasites is a matter of controversy, since iron deficiency protects mice against P. chabaudi, while people with iron deficiency are still susceptible to malaria, but may have an increased parasitaemia if given iron supplementation.