Disparity between ionic mediators of volume regulation and apoptosis in N1E 115 mouse neuroblastoma cells |
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Authors: | O'Reilly Natasha Xia Zhenlei Fiander Hawley Tauskela Joseph Small Daniel L |
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Institution: | Institute for Biological Sciences, National Research Council, Ottawa, Ontario, Canada. |
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Abstract: | Cellular volume loss or shrinkage is a ubiquitous feature of apoptosis and thus may contribute to this form of degeneration. Chloride (Cl(-)) and potassium (K(+)) efflux has been shown to participate in volume regulation and several recent reports have implicated K(+) efflux in apoptotic neuronal death. Here pharmacological inhibitors of various K(+) and Cl(-) channels and transporters were used to decipher the relationship between cellular volume regulation and apoptosis. Following exposure to a hypotonic media, cells swell but over time gradually recover, returning to their original cell volume in a process known as regulatory volume decrease (RVD). RVD in N1E 115 neuroblastoma cells was monitored using time-lapse videomicroscopy, cell size and DNA degradation were followed using flow cytometry and fragmented apoptotic nuclei were visualized using Hoechst staining. RVD was blocked by high K(+), TEA and 4-AP (K(+) channel blockers), DIDS and niflumic acid but not SITS (Cl(-) channel blockers), ethacrynic acid (Cl(-) pump blocker), bumetanide (Na(+)/K(+)/Cl(-) cotransporter blocker) and furosemide (K(+)/Cl(-) cotransport blocker). In contrast, only DIDS and SITS (blockers of the Cl(-)/HCO(3) exchanger) inhibited apoptosis, suggesting that a common mechanistic link between RVD and apoptosis is the Cl(-)/HCO(3) exchanger. Thus, this study does not support the notion that K(+) channels are universal anti-apoptotic targets. Instead, the Cl(-)/HCO(3) exchanger may prove to be a viable target of therapeutic intervention for treating pathological apoptosis and neurodegeneration. |
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Keywords: | K+ channel Cl− channel SITS (4-acetamido-4′ -isothiocyanatostilbene-2 2′ -Disulfonic acid) DIDS (4 4′ -diisothiocyanatostilbene-2 2′ -disulfonic acid) Transporter Exchanger |
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