[en] Highlights: • A melatonin receptor antagonist blocked Ca²⁺ oscillation in P. falciparum and inhibited parasite growth. • P. falciparum development is controlled by Ca²⁺- and cAMP-signaling pathways. • The cAMP-signaling pathway at ring form and late trophozoite stages governs parasite growth of P. falciparum. - Abstract: Plasmodium falciparum spends most of its asexual life cycle within human erythrocytes, where proliferation and maturation occur. Development into the mature forms of P. falciparum causes severe symptoms due to its distinctive sequestration capability. However, the physiological roles and the molecular mechanisms of signaling pathways that govern development are poorly understood. Our previous study showed that P. falciparum exhibits stage-specific spontaneous Calcium (Ca²⁺) oscillations in ring and early trophozoites, and the latter was essential for parasite development. In this study, we show that luzindole (LZ), a selective melatonin receptor antagonist, inhibits parasite growth. Analyses of development and morphology of LZ-treated P. falciparum revealed that LZ severely disrupted intraerythrocytic maturation, resulting in parasite death. When LZ was added at ring stage, the parasite could not undergo further development, whereas LZ added at the trophozoite stage inhibited development from early into late schizonts. Live-cell Ca²⁺ imaging showed that LZ treatment completely abolished Ca²⁺ oscillation in the ring forms while having little effect on early trophozoites. Further, the melatonin-induced cAMP increase observed at ring and late trophozoite stage was attenuated by LZ treatment. These suggest that a complex interplay between IP₃–Ca²⁺ and cAMP signaling pathways is involved in intraerythrocytic development of P. falciparum

[en] Inositol 1,4,5-trisphosphate receptor (IP_3R) is a key regulator of intracellular Ca"2"+ concentration that release Ca"2"+ from Ca"2"+ stores in response to various external stimuli. IP_3R also works as a signal hub which form a platform for interacting with various proteins involved in diverse cell signaling. Previously, we have identified an IP_3R homolog in the parasitic protist, Trypanosoma cruzi (TcIP_3R). Parasites expressing reduced or increased levels of TcIP_3R displayed defects in growth, transformation, and infectivity. In the present study, we established parasitic strains expressing a dominant negative form of TcIP_3R, named DN-TcIP_3R, to further investigate the physiological role(s) of TcIP_3R. We found that the growth of epimastigotes expressing DN-TcIP_3R was significantly slower than that of parasites with TcIP_3R expression levels that were approximately 65% of wild-type levels. The expression of DN-TcIP_3R in epimastigotes induced metacyclogenesis even in the normal growth medium. Furthermore, these epimastigotes showed the presence of dense mitochondria under a transmission electron microscope. Our findings confirm that TcIP_3R is crucial for epimastigote growth, as previously reported. They also suggest that a strong inhibition of the IP_3R-mediated signaling induces metacyclogenesis and that mitochondrial integrity is closely associated with this signaling. - Highlights: • We established T. cruzi strains expressing a dominant negative form of the TcIP_3R. • DN-TcIP_3R expression inhibits epimastigote growth and induces metacyclogenesis. • Microscopic analysis indicated TcIP_3R role in maintaining mitochondrial integrity. • Growth, but not microbial density, was altered by mammalian IP_3R inhibitor (2-APB).