Manganese and copper promote the binding of dopamine to “serotonin binding proteins” in bovine frontal cortex

Abstract

The authors previously reported that Fe 2+ is capable of increasing the binding of dopamine and of serotonin to “serotonin binding proteins” which are present in soluble extracts from calf brain. In this study, it is shown that Mn 2+ and Cu 2+ are also capable of increasing the binding, but for dopamine only. As for Fe 2+, Mn 2+ and Cu 2+ are likely to promote the binding by virtue of their ability to enhance the oxidation of dopamine into dopamine-O-quinone, a derivative which is known to undergo covalent association with sulfhydryl groups of proteins. Data such as the irreversible nature of the majority of the binding, the inhibitory action of reducing agents (sodium ascorbate) and of reagents which contain, or modify sulfhydryl groups (reduced glutathione) are compatible with such a mechanism. The three metal ions are also capable of inactivating part of the binding sites on SBP directly; this effect is more pronounced for Cu 2+ than for Fe 2+ and it is only weak for Mn 2+. The Fe 2+-mediated binding of dopamine is inhibited by the superoxide dismutase enzyme, and it was therefore suggested that Fe 2+ enhances the oxidation of dopamine by virtue of its ability to produce superoxide radicals out of dissolved molecular oxygen. Such a mechanism does not appear to take place in the case of Mn 2+ and Cu 2+. Instead, it is likely that Cu 2+ and dopamine form a complex which is highly susceptible towards oxidation by dissolved molecular oxygen. Mn 2+, on the other hand, can easily be oxidized into Mn 3+, which is capable to oxidize dopamine by itself. Chronic manganese intoxication (from exposure to manganese) and Wilson's disease (related to inadequate elimination of copper) go along with neurological symptoms which are very similar to those encountered in Parkinson's disease. Our data indicate that manganese and copper ions accelerate the oxidation of catecholamines to produce toxic quinones. These quinones could, at least in part, account for the degeneration of dopamininergic neurons in such pathologies.