Cellular calcium deficiency plays a role in neuronal death caused by proteasome inhibitors

Shengzhou Wu, Krzysztof L. Hyrc, Krista L. Moulder, Ying Lin, Timothy Warmke, B. Joy Snider

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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 [Ca 2+]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.

Original languageEnglish
Pages (from-to)1225-1236
Number of pages12
JournalJournal of Neurochemistry
Issue number5
StatePublished - Jun 2009


  • Calcium imaging
  • Capacitative calcium entry
  • Caspase
  • Endoplasmic reticulum
  • Mitochondria


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