Neuronal damage in certain cellular populations in the brain has been linked to oxidative stress accompanied by an elevation in intracellular calcium. Many questions remain about how such oxidative stress occurs and how it affects calcium homeostasis. Glutathione (GSH) is a major regulator of cellular redox status in the brain, and lowered GSH levels have been associated with dopaminergic cell loss in Parkinson's disease (PD). We found that transfection of antisense oligomers directed against glutamylcysteine synthetase (GCS), the rate-limiting enzyme in GSH synthesis, into PC12 cells resulted in decreased GSH and increased levels of ROS. Decreased GSH levels also correlated with an increase in intracellular calcium levels. Data from this study suggest that dopaminergic neurons are very sensitive to decreases in the internal oxidant buffering capacity of the cell caused by reductions in GSH levels, and that alterations in this parameter can result in disruption of calcium homeostasis and cell death. These results may be of particular significance for therapeutic treatment of PD, as those dopaminergic neurons that are spared in this disorder appear to contain the calcium binding protein, calbindin.