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Query: UMLS:C0024530 (
malaria
)
44,886
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Blockage of spontaneous Ca2+ oscillation causes cell death in intraerythrocitic Plasmodium falciparum. 2279 77
Inositol 1,4,5 trisphosphate (IP
3
) signaling plays a crucial role in a wide range of eukaryotic processes. In Plasmodium falciparum, IP
3
elicits Ca
2+
release from intracellular Ca
2+
stores, even though no IP
3
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
3
-dependent Ca
2+
signal. The melatonin-induced cytosolic Ca
2+
([Ca
2+
]
cyt
) increase and
malaria
cell cycle can be blocked by the IP
3
receptor blocker
2-aminoethyl diphenylborinate
(2-APB). However, 2-APB also inhibits store-operated Ca
2+
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
2+
]
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 IP
3
receptor like IP
3
-sponge and an IP
3
sensor such as IRIS proved to be lethal to P. falciparum during intraerythrocytic cycle. The present findings point to an important role of IP
3
-induced Ca
2+
release in intraerythrocytic stage of P. falciparum.
...
PMID:Blocking IP
3
signal transduction pathways inhibits melatonin-induced Ca
2+
signals and impairs P. falciparum development and proliferation in erythrocytes. 2974 36
