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Because it is also known, mainly in non-neuronal systems, that superoxide radicals (O<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>) activate these (and other) kinases and because O<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>generation by mitochondria is in part [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>dependent, we examined in hippocampal neurons the relationship between Ca<jats:sup>2+<\/jats:sup>entry, O<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>production, and kinase activity. We found that, after large stimulus-induced [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>increases, O<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>selectively produced by mitochondria near plasmalemmal sites of Ca<jats:sup>2+<\/jats:sup>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 O<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>inhibition of inactivating protein phosphatases. Conversely, because small [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>increases do not promote mitochondrial respiration and O<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>generation, weak stimuli favor enhanced phosphatase activity, which therefore leads to suppressed kinase activity. Enhanced O<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>production also promoted PKC activity but by a phosphatase-independent pathway. These results suggest that Ca<jats:sup>2+<\/jats:sup>-dependent upregulation of mitochondrial O<jats:sub>2<\/jats:sub><jats:sup>-<\/jats:sup>production may be a general mechanism for linking Ca<jats:sup>2+<\/jats:sup>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.<\/jats:p>","DOI":"10.1523\/jneurosci.3278-04.2004","type":"journal-article","created":{"date-parts":[[2004,12,1]],"date-time":"2004-12-01T19:23:57Z","timestamp":1101929037000},"page":"10878-10887","source":"Crossref","is-referenced-by-count":126,"title":["Strong Calcium Entry Activates Mitochondrial Superoxide Generation, Upregulating Kinase Signaling in Hippocampal Neurons"],"prefix":"10.1523","volume":"24","author":[{"given":"Jarin","family":"Hongpaisan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Winters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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