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Calcium mediated regulation of karyopherin nuclear transport receptors

Oxidative stress disrupts the normal function of cells and severe stress situations can result in apoptosis. A specific effect of oxidant stress is an increase in cellular calcium levels, which can be mimicked by treatment with the drug thapsigargin, which inhibits Ca2+ uptake into the endoplasmic reticulum. We sought to determine if changes in cellular calcium levels induced by thapsigargin disrupted nuclear transport by alteration of karyopherin transport receptors and/or the Ran gradient. Altered Ca2+ levels were monitored using a fluorescence based assay. We found that thapsigargin lead to an accumulation of Ran in the cytoplasm, while prolonged exposure led to cell death. However, the disruption of the Ran gradient could be reversed before the induction of apoptosis and rescue was enhanced by the presence of the calcium chelator BAPTA. Thapsigargin treated cells also exhibited altered location of several karyopherin transport receptors including Transportin, Importin alpha, Importin beta, Crm1, and its cofactor RanBP3. These results suggest that alteration of cellular calcium levels causes disruption of the Ran gradient and variation in karyopherin localization, suggesting that there is a role for calcium as a regulator of Ran‐mediated nuclear transport pathways. Therefore, cellular oxidative stress may result in apoptosis due to the calcium induced alteration of nuclear transport pathways.