Blocking IP signal transduction pathways inhibits melatonin-induced Ca signals and impairs P. falciparum development and proliferation in erythrocytes.

Inositol 1,4,5 trisphosphate (IP) signaling plays a crucial role in a wide range of eukaryotic processes. In Plasmodium falciparum, IP elicits Ca release from intracellular Ca stores, even though no IP 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 IP-dependent Ca signal. The melatonin-induced cytosolic Ca ([Ca]) increase and malaria cell cycle can be blocked by the IP receptor blocker 2-aminoethyl diphenylborinate (2-APB). However, 2-APB also inhibits store-operated Ca 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 [Ca] 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 IP receptor like IP-sponge and an IP sensor such as IRIS proved to be lethal to P. falciparum during intraerythrocytic cycle. The present findings point to an important role of IP-induced Ca release in intraerythrocytic stage of P. falciparum.