Calcium signaling in a low calcium environment: how the intracellular malaria parasite solves the problem

Malaria parasites, Plasmodia, spend most of their asexual life cycle within red blood cells, where they proliferate and mature. The erythrocyte cytoplasm has very low [Ca(2+)] (<100 nM), which is very different from the extracellular environment encountered by most eukaryotic cells. The absence of extracellular Ca(2+) is usually incompatible with normal cell functions and survival. In the present work, we have tested the possibility that Plasmodia overcome the limitation posed by the erythrocyte intracellular environment through the maintenance of a high [Ca(2+)] within the parasitophorous vacuole (PV), the compartment formed during invasion and within which the parasites grow and divide. Thus, Plasmodia were allowed to invade erythrocytes in the presence of Ca(2+) indicator dyes. This allowed selective loading of the Ca(2+) probes within the PV. The [Ca(2+)] within this compartment was found to be ∼40 μM, i.e., high enough to be compatible with a normal loading of the Plasmodia intracellular Ca(2+) stores, a prerequisite for the use of a Ca(2+)-based signaling mechanism. We also show that reduction of extracellular [Ca(2+)] results in a slow depletion of the [Ca(2+)] within the PV. A transient drop of [Ca(2+)] in the PV for a period as short as 2 h affects the maturation process of the parasites within the erythrocytes, with a major reduction 48 h later in the percentage of schizonts, the form that re-invades the red blood cells.