Glutamate-induced calcium increase mediates magnesium release from mitochondria in rat hippocampal neurons

✍ Scribed by Yutaka Shindo; Ai Fujimoto; Kohji Hotta; Koji Suzuki; Kotaro Oka

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 429 KB
• Volume: 88
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.22467

✦ Synopsis

Excess administration of glutamate is known to induce Ca 21 overload in neurons, which is the first step in excitotoxicity. Although some reports have suggested a role for Mg 21 in the excitotoxicity, little is known about its actual contribution. To investigate the role of Mg 21 in the excitotoxicity, we simultaneously measured intracellular Ca 21 and Mg 21 , using fluorescent dyes, Fura red, a fluorescent Ca 21 probe, and KMG-104, a highly selective fluorescent Mg 21 probe developed by our group, respectively. Administration of 100 lM glutamate supplemented with 10 lM glycine to rat hippocampal neurons induced an increase in intracellular Mg 21 concentration ([Mg 21 ] i ). Extracellular Mg 21 was not required for this glutamate-induced increase in [Mg 21 ] i , and no increase in intracellular Ca 21 concentration ([Ca 21 ] i ) or [Mg 21 ] i was observed in neurons in nominally Ca 21 -free medium. Application of 5 lM carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), an uncoupler of mitochondrial inner membrane potential, also elicited increases in [Ca 21 ] i and [Mg 21 ] i . Subsequent administration of glutamate and glycine following FCCP treatment did not induce a further increase in [Mg 21 ] i but did induce an additive increase in [Ca 21 ] i . Moreover, the glutamate-induced increase in [Mg 21 ] i was observed only in mitochondria localized areas. These results support the idea that glutamate is able to induced Mg 21 efflux from mitochondria to the cytosol. Furthermore, pretreatment with Ru360, an inhibitor of the mitochondrial Ca 21 uniporter, prevented this [Mg 21 ] i increase. These results indicate that glutamate-induced increases in [Mg 21 ] i result from the Mg 21 release from mitochondria and that Ca 21 accumulation in the mitochondria is required for this Mg 21 release.