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- Augustynek 2018 Int J Mol Sci + (Potassium channel openers (KCOs) have been … Potassium channel openers (KCOs) have been shown to play a role in cytoprotection through the activation of mitochondrial potassium channels. Recently, in several reports, a number of data has been described as off-target actions for KCOs. In the present study, we investigated the effects of BK<sub>Ca</sub> channel openers CGS7181, CGS7184, NS1619, and NS004 in neuronal cells. For the purpose of this research, we used a rat brain, the mouse hippocampal HT22 cells, and the human astrocytoma U-87 MG cell line. We showed that CGS7184 activated the mitochondrial BK<sub>Ca</sub> (mitoBK<sub>Ca</sub>) channel in single-channel recordings performed on astrocytoma mitoplasts. Moreover, when applied to the rat brain homogenate or isolated rat brain mitochondria, CGS7184 increased the oxygen consumption rate, and can thus be considered a potentially cytoprotective agent. However, experiments on intact neuronal HT22 cells revealed that both CGS7181 and CGS7184 induced HT22 cell death in a concentration- and time-dependent manner. By contrast, we did not observe cell death when NS1619 or NS004 was applied. CGS7184 toxicity was not abolished by BK<sub>Ca</sub> channel inhibitors, suggesting that the observed effects were independent of a BK<sub>Ca</sub>-type channel activity. CGS7184 treatment resulted in an increase of cytoplasmic Ca<sup>2+</sup> concentration that likely involved efflux from internal calcium stores and the activation of calpains (calcium-dependent proteases). The cytotoxic effect of the channel opener was partially reversed by a calpain inhibitor. Our data show that KCOs under study not only activate mitoBK<sub>Ca</sub> channels from brain tissue, but also induce cell death when used in cellular models. activate mitoBK<sub>Ca</sub> channels from brain tissue, but also induce cell death when used in cellular models.)