A comprehensive atlas of the topography of functional groups of the dopamine transporter.

The neuronal dopamine transporter (DAT) is a transmembrane transporter that clears DA from the synaptic cleft. Knowledge of DAT functional group topography is a prerequisite for understanding the molecular basis of transporter function, the actions of psychostimulant drugs, and mechanisms of dopaminergic neurodegeneration. Information concerning the molecular interactions of drugs of abuse (such as cocaine, amphetamine, and methamphetamine) with the DAT at the functional group level may also aid in the development of compounds useful as therapeutic agents for the treatment of drug abuse. This review will provide a cumulative and comprehensive focus on the amino acid functional group topography of the rat and human DATs, as revealed by protein chemical modification and the techniques of site-directed mutagenesis. The results from these studies, represented mostly by site-directed mutagenesis, can be classified into several main categories: modifications without substantial affects on substrate transport, DAT membrane expression, or cocaine analog binding; those modifications which alter both substrate transport and cocaine analog binding; and those that affect DAT membrane expression. Finally, some modifications can selectively affect either substrate transport or cocaine analog binding. Taken together, these literature results show that domains for substrates and cocaine analogs are formed by interactions with multiple and sometimes distinct DAT functional groups.