Melatonin and IP3-induced Ca2+ Release from Intracellular Stores in the Malaria Parasite Plasmodium falciparum within Infected Red Blood Cells
Melatonin and IP3-induced Ca2+ Release from Intracellular Stores in the Malaria Parasite Plasmodium falciparum within Infected Red Blood Cells
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DOI：
10.1074/jbc.m110.188474
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发表时间：
2011-02-18
影响因子：
4.8
通讯作者：
Thomas, Andrew P.
中科院分区：
文献类型：
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作者：
Alves, Eduardo;Bartlett, Paula J.;Thomas, Andrew P.
IP 3依赖性Ca 2+信号传导控制高等真核生物中的无数细胞过程，并且类似的信号传导途径在疟原虫（引起疟疾的细胞内寄生虫）中进化上保守。我们已经报道，分离的，透化的夏氏疟原虫，释放Ca 2+后，加入外源性IP 3。在本研究中，我们研究了IP 3信号通路是否在完整的恶性疟原虫中起作用，恶性疟原虫是主要的致病人类疟疾寄生虫。将滋养体阶段的恶性疟原虫感染的红细胞（RBC）同时加载有Ca 2+指示剂Fluo-4/AM和笼状IP 3。IP 3的光解释放引起了一个短暂的Ca 2+的增加，在红细胞内的完整的寄生虫的胞质溶胶。选择性地释放寄生虫的细胞内Ca 2+池，使用毒胡萝卜素消耗内质网（ER）Ca 2+和抗疟氯喹消耗Ca 2+从酸钙体。这些数据表明，ER是主要的IP 3-敏感的Ca 2+库。先前的研究表明，人类宿主激素褪黑激素通过Ca 2+依赖性途径调节恶性疟原虫细胞周期。在本研究中，我们证明，褪黑激素增加肌醇-多磷酸生产在完整的红细胞内寄生虫。此外，在感染的红细胞中，褪黑激素和IP 3释放的Ca 2+反应是相互排斥的。总之，这些数据提供的证据表明，褪黑激素激活PLC产生IP 3和开放ER定位的IP 3敏感的Ca 2+通道在恶性疟原虫。该受体信号通路可能参与寄生虫细胞周期进程的调控和同步化。
IP3-dependent Ca2+ signaling controls a myriad of cellular processes in higher eukaryotes and similar signaling pathways are evolutionarily conserved in Plasmodium, the intracellular parasite that causes malaria. We have reported that isolated, permeabilized Plasmodium chabaudi, releases Ca2+ upon addition of exogenous IP3. In the present study, we investigated whether the IP3 signaling pathway operates in intact Plasmodium falciparum, the major disease-causing human malaria parasite. P. falciparum-infected red blood cells (RBCs) in the trophozoite stage were simultaneously loaded with the Ca2+ indicator Fluo-4/AM and caged-IP3. Photolytic release of IP3 elicited a transient Ca2+ increase in the cytosol of the intact parasite within the RBC. The intracellular Ca2+ pools of the parasite were selectively discharged, using thapsigargin to deplete endoplasmic reticulum (ER) Ca2+ and the antimalarial chloroquine to deplete Ca2+ from acidocalcisomes. These data show that the ER is the major IP3-sensitive Ca2+ store. Previous work has shown that the human host hormone melatonin regulates P. falciparum cell cycle via a Ca2+-dependent pathway. In the present study, we demonstrate that melatonin increases inositol-polyphosphate production in intact intraerythrocytic parasite. Moreover, the Ca2+ responses to melatonin and uncaging of IP3 were mutually exclusive in infected RBCs. Taken together these data provide evidence that melatonin activates PLC to generate IP3 and open ER-localized IP3-sensitive Ca2+ channels in P. falciparum. This receptor signaling pathway is likely to be involved in the regulation and synchronization of parasite cell cycle progression.