Chelation of extracellular calcium-induced cell death was prevented by glycogen synthase kinase-3 inhibitors in PC12 cells

Cell Mol Neurobiol. 2010 Mar;30(2):193-8. doi: 10.1007/s10571-009-9442-y. Epub 2009 Aug 18.


Calcium ion is a secondary messenger that mediates a variety of physiological responses of neurons, including cell survival responses. To determine the role of calcium in regulating neuronal survival and death, we examined whether chelation of extracellular calcium with EGTA induces caspase-dependent apoptotic cell death and whether glycogen synthase kinase-3 is involved in EGTA-induced cell death in PC12 cells. EGTA increased apoptotic cell death with morphological changes characterized by cell shrinkage and nuclear condensation and fragmentation accompanied by caspase activation. EGTA increased GRP78 protein expression, suggesting that EGTA induces ER stress. Glycogen synthase kinase-3 inhibitors prevented EGTA-induced apoptosis. In addition, nerve growth factor and insulin growth factor-I completely blocked EGTA-induced cell death. Moreover, caspase-3 activation was inhibited by glycogen synthase kinase-3 inhibitors. These results suggest that chelation of extracellular calcium with EGTA induces caspase-dependent apoptosis, and the activation of glycogen synthase kinase-3 is involved in the death of PC12 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Benzazepines / metabolism
  • Calcium* / metabolism
  • Calcium* / pharmacology
  • Caspases / metabolism
  • Cell Death / drug effects*
  • Chelating Agents / metabolism*
  • Egtazic Acid / metabolism
  • Enzyme Activation
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Heat-Shock Proteins / metabolism
  • Indoles / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Maleimides / metabolism
  • Nerve Growth Factor / metabolism
  • PC12 Cells
  • Rats


  • Benzazepines
  • Chelating Agents
  • GRP78 protein, rat
  • Heat-Shock Proteins
  • Indoles
  • Maleimides
  • SB 216763
  • alsterpaullone
  • Egtazic Acid
  • Insulin-Like Growth Factor I
  • Nerve Growth Factor
  • Glycogen Synthase Kinase 3
  • Caspases
  • Calcium