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Arachidonic acid induces both Na+ and Ca2+ entry resulting in apoptosis
Authors:Fang Kwang-Ming  Chang Wei-Luen  Wang Su-Mei  Su Ming-Jai  Wu Mei-Lin
Institution:Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan;
Department of Dental Laboratory Technology, Central Taiwan University of Science and Technology, Taichung, Taiwan;
Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan;
Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
Abstract: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.
Keywords:apoptosis  arachidonate  mitochondria  neurons
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