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Mitochondrial BK Channel Openers CGS7181 and CGS7184 Exhibit Cytotoxic Properties
Bartłomiej Augustynek1,2, Piotr Koprowski3, Daria Rotko4
1Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur St., 02-093 Warsaw, Poland. bartlomiej.augustynek@ibmm.unibe.ch.
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.
Insights
Potassium channel openers (KCOs) can activate mitochondrial channels for cytoprotection. However, some KCOs, like CGS7184, induce neuronal cell death through calcium signaling, not BKCa channel activity.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Potassium channel openers (KCOs) are known for cytoprotective effects via mitochondrial potassium channel activation.
- Recent studies suggest KCOs may exhibit off-target actions.
- The specific effects of BKCa channel openers in neuronal cells require further investigation.
Purpose of the Study:
- To investigate the effects of BKCa channel openers (CGS7181, CGS7184, NS1619, NS004) on neuronal cells.
- To determine if these openers activate mitochondrial BKCa channels (mitoBKCa) and affect cellular respiration.
- To elucidate the mechanisms underlying any observed cellular toxicity.
Main Methods:
- Single-channel recordings on astrocytoma mitoplasts.
- Measurement of oxygen consumption rate in brain homogenates and isolated mitochondria.
- Cell viability assays on HT22 and U-87 MG cell lines.
- Intracellular calcium concentration measurements and calpain activity assessment.
Main Results:
- CGS7184 activated mitoBKCa channels and increased oxygen consumption in brain preparations, suggesting cytoprotective potential.
- CGS7181 and CGS7184 induced concentration- and time-dependent cell death in HT22 cells.
- NS1619 and NS004 did not cause cell death.
- CGS7184 toxicity was independent of BKCa channel inhibition, linked to increased cytoplasmic calcium and calpain activation.
Conclusions:
- While some KCOs activate mitoBKCa channels and show potential for cytoprotection, others can induce neuronal cell death.
- The cytotoxicity of CGS7184 is mediated by calcium dysregulation and calpain activation, independent of BKCa channel activity.
- These findings highlight the complex and potentially dual role of KCOs in neuronal cells, necessitating careful consideration of off-target effects.
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