Drs Ming-Jai Su and Mei-Lin Wu have equal contribution to this work.
Arachidonic acid induces both Na+ and Ca2+ entry resulting in apoptosis
Version of Record online: 8 OCT 2007
© 2007 The Authors
Journal of Neurochemistry
Volume 104, Issue 5, pages 1177–1189, March 2008
How to Cite
Fang, K.-M., Chang, W.-L., Wang, S.-M., Su, M.-J. and Wu, M.-L. (2008), Arachidonic acid induces both Na+ and Ca2+ entry resulting in apoptosis. Journal of Neurochemistry, 104: 1177–1189. doi: 10.1111/j.1471-4159.2007.05022.x
- Issue online: 8 OCT 2007
- Version of Record online: 8 OCT 2007
- Received May 21, 2007; revised manuscript received August 25, 2007; accepted September 25, 2007.
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.