Cellular calcium deficiency plays a role in neuronal death caused by proteasome inhibitors
Article first published online: 14 MAR 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 109, Issue 5, pages 1225–1236, June 2009
How to Cite
Wu, S., Hyrc, K. L., Moulder, K. L., Lin, Y., Warmke, T. and Snider, B. J. (2009), Cellular calcium deficiency plays a role in neuronal death caused by proteasome inhibitors. Journal of Neurochemistry, 109: 1225–1236. doi: 10.1111/j.1471-4159.2009.06037.x
- Issue published online: 12 MAY 2009
- Article first published online: 14 MAR 2009
- Received January 22, 2009; revised manuscript received March 3, 2009; accepted March 5, 2009.
- calcium imaging;
- capacitative calcium entry;
- endoplasmic reticulum;
Cytosolic Ca2+ concentration ([Ca2+]i) is reduced in cultured neurons undergoing neuronal death caused by inhibitors of the ubiquitin proteasome system. Activation of calcium entry via voltage-gated Ca2+ channels restores cytosolic Ca2+ levels and reduces this neuronal death (Snider et al. 2002). We now show that this reduction in [Ca2+]i is transient and occurs early in the cell death process, before activation of caspase 3. Agents that increase Ca2+ influx such as activation of voltage-gated Ca2+ channels or stimulation of Ca2+ entry via the plasma membrane Na–Ca exchanger attenuate neuronal death only if applied early in the cell death process. Cultures treated with proteasome inhibitors had reduced current density for voltage-gated Ca2+ channels and a less robust increase in [Ca2+]i after depolarization. Levels of endoplasmic reticulum Ca2+ were reduced and capacitative Ca2+ entry was impaired early in the cell death process. Mitochondrial Ca2+ was slightly increased. Preventing the transfer of Ca2+ from mitochondria to cytosol increased neuronal vulnerability to this death while blockade of mitochondrial Ca2+ uptake via the uniporter had no effect. Programmed cell death induced by proteasome inhibition may be caused in part by an early reduction in cytosolic and endoplasmic reticulum Ca2+, possibly mediated by dysfunction of voltage-gated Ca2+ channels. These findings may have implications for the treatment of disorders associated with protein misfolding in which proteasome impairment and programmed cell death may occur.