Arachidonic acid induces both Na+and Ca2+entry resulting in apoptosis
| Autor: | Mei-Lin Wu, Ming-Jai Su, Kwang-Ming Fang, Wei-Luen Chang, Su-Mei Wang |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Intracellular Fluid
Male Sodium chemistry.chemical_element Apoptosis Mitochondrion Biochemistry Ion Channels Cellular and Molecular Neuroscience chemistry.chemical_compound Cyclosporin a Animals Rats Wistar Uniporter Neurons Arachidonic Acid biology Cytochrome c Molecular biology Rats chemistry Mitochondrial permeability transition pore biology.protein Ruthenium Compounds Calcium Female Arachidonic acid |
| Zdroj: | Journal of Neurochemistry. 104:1177-1189 |
| ISSN: | 1471-4159 0022-3042 |
| DOI: | 10.1111/j.1471-4159.2007.05022.x |
| Popis: | Marked accumulation of arachidonic acid (AA) and intracellular Ca2+ and Na+ overloads are seen during brain ischemia. In this study, we show that, in neurons, AA induces cytosolic Na+ ([Na+](cyt)) and Ca2+ ([Ca2+](cyt)) overload via a non-selective cation conductance (NSCC), resulting in mitochondrial [Na+](m) and [Ca2+](m) overload. Another two types of free fatty acids, including oleic acid and eicosapentaenoic acid, induced a smaller increase in the [Ca2+](i) and [Na+](i). RU360, a selective inhibitor of the mitochondrial Ca2+ uniporter, inhibited the AA-induced [Ca2+](m) and [Na+](m) overload, but not the [Ca2+](cyt) and [Na+](cyt) overload. The [Na+](m) overload was also markedly inhibited by either Ca2+-free medium or CGP3715, a selective inhibitor of the mitochondrial Na+(cyt)-Ca2+(m) exchanger. Moreover, RU360, Ca2+-free medium, Na+-free medium, or cyclosporin A (CsA) largely prevented AA-induced opening of the mitochondrial permeability transition pore, cytochrome c release, and caspase 3-dependent neuronal apoptosis. Importantly, Na+-ionophore/Ca2+-free medium, which induced [Na+](m) overload, but not [Ca2+](m) overload, also caused cyclosporin A-sensitive mitochondrial permeability transition pore opening, resulting in caspase 3-dependent apoptosis, indicating that [Na+](m) overload per se induced apoptosis. Our results therefore suggest that AA-induced [Na+](m) overload, acting via activation of the NSCC, is an important upstream signal in the mitochondrial-mediated apoptotic pathway. The NSCC may therefore act as a potential neuronal death pore which is activated by AA accumulation under pathological conditions. |
| Databáze: | OpenAIRE |
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