Blockage of spontaneous Ca2+ oscillation causes cell death in intraerythrocitic Plasmodium falciparum

• Published in: PloS one Vol. 7; no. 7; p. e39499
• Main Authors: Enomoto, Masahiro, Kawazu, Shin-ichiro, Kawai, Satoru, Furuyama, Wakako, Ikegami, Tohru, Watanabe, Jun-ichi, Mikoshiba, Katsuhiko
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06-07-2012; Public Library of Science (PLoS)
• Subjects: Adenosine; Antimalarials - pharmacology; Biology; Blockage; Boron Compounds - pharmacology; Brain research; Calcium (extracellular); Calcium imaging; Calcium ions; Calcium Signaling; Calcium signalling; Cell Death; Chloroquine; Chloroquine - pharmacology; Cloning; Cytoplasm; Developmental stages; Drug development; Drug Resistance; Electron micrographs; Erythrocytes; Erythrocytes - metabolism; Erythrocytes - parasitology; Fluorescence; Food; Humans; Hypotheses; Infectious diseases; Inositol 1,4,5-trisphosphate receptors; Kinases; Laboratories; Malaria; Maturation; Medicine; Melatonin; Molecular modelling; Morbidity; Morphology; Neurobiology; Neurosciences; Oscillations; Parasites; Plant cells; Plasmodium; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - growth & development; Plasmodium falciparum - metabolism; Proteins; Puberty; Science; Signal transduction; Trophozoites - drug effects; Vector-borne diseases; Veterinary medicine; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0039499

Malaria remains one of the world's most important infectious diseases and is responsible for enormous mortality and morbidity. Resistance to antimalarial drugs is a challenging problem in malaria control. Clinical malaria is associated with the proliferation and development of Plasmodium parasites in human erythrocytes. Especially, the development into the mature forms (trophozoite and schizont) of Plasmodium falciparum (P. falciparum) causes severe malaria symptoms due to a distinctive property, sequestration which is not shared by any other human malaria. Ca(2+) is well known to be a highly versatile intracellular messenger that regulates many different cellular processes. Cytosolic Ca(2+) increases evoked by extracellular stimuli are often observed in the form of oscillating Ca(2+) spikes (Ca(2+) oscillation) in eukaryotic cells. However, in lower eukaryotic and plant cells the physiological roles and the molecular mechanisms of Ca(2+) oscillation are poorly understood. Here, we showed the observation of the inositol 1,4,5-trisphospate (IP(3))-dependent spontaneous Ca(2+) oscillation in P. falciparum without any exogenous extracellular stimulation by using live cell fluorescence Ca(2+) imaging. Intraerythrocytic P. falciparum exhibited stage-specific Ca(2+) oscillations in ring form and trophozoite stages which were blocked by IP(3) receptor inhibitor, 2-aminoethyl diphenylborinate (2-APB). Analyses of parasitaemia and parasite size and electron micrograph of 2-APB-treated P. falciparum revealed that 2-APB severely obstructed the intraerythrocytic maturation, resulting in cell death of the parasites. Furthermore, we confirmed the similar lethal effect of 2-APB on the chloroquine-resistant strain of P. falciparum. To our best knowledge, we for the first time showed the existence of the spontaneous Ca(2+) oscillation in Plasmodium species and clearly demonstrated that IP(3)-dependent spontaneous Ca(2+) oscillation in P. falciparum is critical for the development of the blood stage of the parasites. Our results provide a novel concept that IP(3)/Ca(2+) signaling pathway in the intraerythrocytic malaria parasites is a promising target for antimalarial drug development.