Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin
| Autor: | Lesley Wolf, M. Cabezas, Geoffrey S. Dow, Diana Caridha, Debra L. Yourick, Thomas H. Hudson |
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| Rok vydání: | 2008 |
| Předmět: |
chemistry.chemical_element
Calcium Biology Pharmacology Neuroprotection Cell Line Antimalarials chemistry.chemical_compound Animals Homeostasis Pharmacology (medical) Inositol phosphate Receptor Mechanisms of Action: Physiological Effects Cells Cultured Cerebral Cortex Neurons chemistry.chemical_classification Calcium metabolism Ionomycin Macrophages Endoplasmic reticulum Glutamate receptor Rats Mefloquine Infectious Diseases chemistry |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 52:684-693 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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