Glutathione is involved in the granular storage of dopamine in rat PC 12 pheochromocytoma cells: implications for the pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is characterized by degeneration of dopamine (DA)-containing nigro-striatal neurons. Loss of the antioxidant glutathione (GSH) has been implicated in the pathogenesis of PD. Previously, we showed that the oxidant hydrogen peroxide inhibits vesicular uptake of DA in nigro-striatal neurons. Hydrogen peroxide is scavenged by GSH and, therefore, we investigated a possible link between the process of vesicular storage of DA and GSH metabolism. For this purpose, we used rat pheochromocytoma-derived PC12 cells, a model system applied extensively for studying monoamine storage mechanisms. We show that depletion of endogenous DA stores with reserpine was accompanied in PC12 cells by a long-lasting, significant increase in GSH content the extent of which appeared to be inversely related to the rate of GSH synthesis. A similar increase in GSH content was observed after depletion of DA stores with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine. In the presence of alpha-methyl-p-tyrosine, refilling of the DA stores by exogenous DA reduced GSH content back to control level. Lowering of PC12 GSH content, via blockade of its synthesis with buthionine sulfoximine, however, led to a significantly decreased accumulation of exogenous [3H]DA without affecting uptake of the acetylcholine precursor [14C]choline. These data suggest that GSH is involved in the granular storage of DA in PC12 cells and that, considering the molecular characteristics of the granular transport system, it is likely that GSH is used to protect susceptible parts of this system against (possibly DA-induced) oxidative damage.