Mefloquine-induced disruption of calcium homeostasis in mammalian cells is similar to that induced by ionomycin
Mefloquine-induced disruption of calcium homeostasis in mammalian cells is similar to that induced by ionomycin
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DOI：
10.1128/aac.00874-07
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发表时间：
2008-02-01
影响因子：
4.9
通讯作者：
Dow, G. S.
中科院分区：
文献类型：
--
作者：
Caridha, D.;Yourick, D.;Dow, G. S.
在以前的研究中，我们已经证明甲氟喹通过耗尽内质网(ER)储备物，随后外部钙跨质膜内流来破坏神经元的钙稳态。在本研究中，我们探索了关于甲氟喹作用机制(S)的两个假说。首先，我们研究了甲氟喹激活非N-甲基-D-天冬氨酸受体和肌醇磷酸3(IP3)信号通路导致内质网钙释放的可能性。其次，我们比较了甲氟喹和离子霉素对神经细胞和非神经细胞钙稳态的破坏作用。已知离子霉素释放内质网钙储存(通过一种未知的机制)，从而诱导容量性钙内流(CCE)。在放射性配基结合分析中，甲氟喹对几种谷氨酸受体亚型的已知结合部位没有亲和力。谷氨酸受体拮抗剂的神经保护作用模式与甲氟喹不同。甲氟喹和离子霉素在神经元和巨噬细胞中均表现出剂量相关和性质相似的钙稳态破坏。CCE抑制剂以剂量相关的方式阻断外源性钙离子的内流。甲氟喹和离子霉素都上调了IP3途径，我们认为这种方式是次要的CCE。总而言之，这些数据表明，甲氟喹不会激活谷氨酸受体，它以类似于离子霉素的方式扰乱哺乳动物细胞中的钙稳态。
In previous studies, we have shown that mefloquine disrupts calcium homeostasis in neurons by depletion of endoplasmic reticulum (ER) stores, followed by an influx of external calcium across the plasma membrane. In this study, we explore two hypotheses concerning the mechanism(s) of action of mefloquine. First, we investigated the possibility that mefloquine activates non-N-methyl-D-aspartic acid receptors and the inositol phosphate 3 (IP3) signaling cascade leading to ER calcium release. Second, we compared the disruptive effects of mefloquine on calcium homeostasis to those of ionomycin in neuronal and nonneuronal cells. Ionomycin is known to discharge the ER calcium store (through an undefined mechanism), which induces capacitative calcium entry (CCE). In radioligand binding assays, mefloquine showed no affinity for the known binding sites of several glutamate receptor subtypes. The pattern of neuroprotection induced by a panel of glutamate receptor antagonists was dissimilar to that of mefloquine. Both mefloquine and ionomycin exhibited dose-related and qualitatively similar disruptions of calcium homeostasis in both neurons and macrophages. The influx of external calcium was blocked by the inhibitors of CCE in a dose-related fashion. Both mefloquine and ionomycin upregulated the IP3 pathway in a manner that we interpret to be secondary to CCE. Collectively, these data suggest that mefloquine does not activate glutamate receptors and that it disrupts calcium homeostasis in mammalian cells in a manner similar to that of ionomycin.