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The Journal of Neuroscience, December 1, 2004, 24(48):10878-10887; doi:10.1523/JNEUROSCI.3278-04.2004

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Cellular/Molecular
Strong Calcium Entry Activates Mitochondrial Superoxide Generation, Upregulating Kinase Signaling in Hippocampal Neurons

Jarin Hongpaisan, Christine A. Winters, and S. Brian Andrews

Laboratory of Neurobiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-4062.

Large increases in cytosolic free Ca²⁺ ([Ca²⁺]_i) activate several kinases that are important for neuronal plasticity, including Ca²⁺/calmodulin-dependent kinase II (CaMKII), protein kinase A (PKA), and protein kinase C (PKC). Because it is also known, mainly in non-neuronal systems, that superoxide radicals (O₂^-) activate these (and other) kinases and because O₂^- generation by mitochondria is in part [Ca²⁺]_i dependent, we examined in hippocampal neurons the relationship between Ca²⁺ entry, O₂^- production, and kinase activity. We found that, after large stimulus-induced [Ca²⁺]_i increases, O₂^- selectively produced by mitochondria near plasmalemmal sites of Ca²⁺ entry acts as a modulator to upregulate the two kinases, namely, CaMKII and PKA, whose activities are directly or indirectly phosphorylation dependent. The common mechanism involves O₂^- inhibition of inactivating protein phosphatases. Conversely, because small [Ca²⁺]_i increases do not promote mitochondrial respiration and O₂^- generation, weak stimuli favor enhanced phosphatase activity, which therefore leads to suppressed kinase activity. Enhanced O₂^- production also promoted PKC activity but by a phosphatase-independent pathway. These results suggest that Ca²⁺-dependent upregulation of mitochondrial O₂^- production may be a general mechanism for linking Ca²⁺ entry to enhanced kinase activity and therefore to synaptic plasticity. This mechanism also represents yet another way that mitochondria, acting as calcium sensors, can play a role in neuronal signal transduction.

Key words: superoxide; reactive oxygen species; mitochondria; calcium; calcium signaling; calcium/calmodulin-dependent protein kinase II; CaMKII; protein kinase A; PKA; protein kinase C; PKC; protein phosphatases; hippocampus

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Received Aug 10, 2004; revised October 8, 2004; accepted October 20, 2004.

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