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Int. J. Mol. Sci. 2018, 19(2), 353; https://doi.org/10.3390/ijms19020353

Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic Properties

1
Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland
2
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, CH-3012 Bern, Switzerland
3
Department of Experimental Epileptology and Cognition Research and Department of Epileptology, University of Bonn, 25 Sigmund-Freud Strasse, D-53105 Bonn, Germany
*
Author to whom correspondence should be addressed.
Received: 16 November 2017 / Revised: 15 January 2018 / Accepted: 22 January 2018 / Published: 25 January 2018
(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)
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Abstract

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 BKCa 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 BKCa (mitoBKCa) 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 BKCa channel inhibitors, suggesting that the observed effects were independent of a BKCa-type channel activity. CGS7184 treatment resulted in an increase of cytoplasmic Ca2+ 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 mitoBKCa channels from brain tissue, but also induce cell death when used in cellular models. View Full-Text
Keywords: potassium channel openers; mitoBKCa channel; neuronal cells; cytotoxicity; mitochondria potassium channel openers; mitoBKCa channel; neuronal cells; cytotoxicity; mitochondria
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Augustynek, B.; Koprowski, P.; Rotko, D.; Kunz, W.S.; Szewczyk, A.; Kulawiak, B. Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic Properties. Int. J. Mol. Sci. 2018, 19, 353.

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