Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic Properties
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 ch...
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2018-01-01
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| author | Bartłomiej Augustynek Piotr Koprowski Daria Rotko Wolfram S. Kunz Adam Szewczyk Bogusz Kulawiak |
| author_facet | Bartłomiej Augustynek Piotr Koprowski Daria Rotko Wolfram S. Kunz Adam Szewczyk Bogusz Kulawiak |
| author_sort | Bartłomiej Augustynek |
| collection | DOAJ |
| description | 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. |
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| spelling | doaj.art-bdb30b56614b41b196e0cb4696ad06e02022-12-22T03:08:54ZengMDPI AGInternational Journal of Molecular Sciences1422-00672018-01-0119235310.3390/ijms19020353ijms19020353Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic PropertiesBartłomiej Augustynek0Piotr Koprowski1Daria Rotko2Wolfram S. Kunz3Adam Szewczyk4Bogusz Kulawiak5Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, PolandLaboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, PolandLaboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, PolandDepartment of Experimental Epileptology and Cognition Research and Department of Epileptology, University of Bonn, 25 Sigmund-Freud Strasse, D-53105 Bonn, GermanyLaboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, PolandLaboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, PolandPotassium 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.http://www.mdpi.com/1422-0067/19/2/353potassium channel openersmitoBKCa channelneuronal cellscytotoxicitymitochondria |
| spellingShingle | Bartłomiej Augustynek Piotr Koprowski Daria Rotko Wolfram S. Kunz Adam Szewczyk Bogusz Kulawiak Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic Properties International Journal of Molecular Sciences potassium channel openers mitoBKCa channel neuronal cells cytotoxicity mitochondria |
| title | Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic Properties |
| title_full | Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic Properties |
| title_fullStr | Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic Properties |
| title_full_unstemmed | Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic Properties |
| title_short | Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic Properties |
| title_sort | mitochondrial bk channel openers cgs7181 and cgs7184 exhibit cytotoxic properties |
| topic | potassium channel openers mitoBKCa channel neuronal cells cytotoxicity mitochondria |
| url | http://www.mdpi.com/1422-0067/19/2/353 |
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