Inositol 1,4,5 trisphosphate (IP3) signaling plays a crucial role in a wide range of eukaryotic processes. In Plasmodium falciparum, IP3 elicits Ca2+ release from intracellular Ca2+ stores, even though no
IP3 receptor homolog has been identified to date. The human host
hormone melatonin plays a key role in entraining the P. falciparum life cycle in the intraerythrocytic stages, apparently through an IP3-dependent Ca2+ signal. The
melatonin-induced cytosolic Ca2+ ([Ca2+]cyt) increase and
malaria cell cycle can be blocked by the
IP3 receptor blocker
2-aminoethyl diphenylborinate (2-APB). However, 2-APB also inhibits store-operated Ca2+ entry (SOCE). Therefore, we have used two novel 2-APB derivatives,
DPB162-AE and DPB163-AE, which are 100-fold more potent than 2-APB in blocking SOCE in mammalian cells, and appear to act by interfering with clustering of STIM
proteins. In the present work we report that
DPB162-AE and DPB163-AE block the [Ca2+]cyt rise in response to
melatonin in P. falciparum, but only at high concentrations. These compounds also block SOCE in the parasite at similarly high concentrations suggesting that P. falciparum SOCE is not activated in the same way as in mammalian cells. We further find that
DPB162-AE and DPB163-AE affect the development of the intraerythrocytic parasites and invasion of new red blood cells. Our efforts to episomally express
proteins that compete with native
IP3 receptor like IP3-sponge and an IP3 sensor such as IRIS proved to be lethal to P. falciparum during intraerythrocytic cycle. The present findings point to an important role of IP3-induced Ca2+ release in intraerythrocytic stage of P. falciparum.