title: An interplay between 2 signaling pathways: melatonin-cAMP and IP3-Ca2+ signaling pathways control intraerythrocytic development of the malaria parasite Plasmodium 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 (Ca(2+)) 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 Ca(2+) imaging showed that LZ treatment completely abolished Ca(2+) 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-Ca(2+) and cAMP signaling pathways is involved in intraerythrocytic development of P. falciparum.
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Furuyama
authors.affiliation: Princess Margaret Cancer Centre, Department of Medical Biophysics, University of Toronto, M5G1L7 Toronto, Ontario, Canada.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Enomoto
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan.
authors.forename: Ehab
authors.initials: E
authors.lastname: Mossaad
authors.affiliation: Laboratory of Tropical Medicine and Parasitology, Dokkyo Medical University, Mibu, Tochigi 321-0293, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kawai
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.affiliation: National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Hokkaido 080-8555, Japan. Electronic address: skawazu@obihiro.ac.jp.
authors.forename: Shin-ichiro
authors.initials: S
authors.lastname: Kawazu
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D007097:Imines / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D016778:Malaria, Falciparum / Q000469:parasitology; D008550:Melatonin / Q000378:metabolism*; D008954:Models, Biological; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism*; D044094:Receptors, Melatonin / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014363:Tryptamines / Q000494:pharmacology
chemical_list: D007097:Imines; D044094:Receptors, Melatonin; D014363:Tryptamines; C057154:luzindole; C014925:RMI 12330A; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D008550:Melatonin
keywords: Ca(2+) oscillations; Live cell imaging; Malaria; Plasmodium falciparum; Signaling pathway; cAMP