Abstract
The plasma membrane monoamine transporters terminate neurotransmission by removing dopamine, norepinephrine, or serotonin from the synaptic cleft between neurons. Specific inhibitors for these transporters, including the abused psychostimulants cocaine and amphetamine and the tricyclic and SSRI classes of antidepressants, exert their physiological effects by interfering with synaptic uptake and thus prolonging the actions of the monoamine. Pharmacological, biochemical, and immunological characterization of the many site-directed, chimeric, and deletion mutants generated for the plasma membrane monoamine transporters have revealed much about the commonalities and dissimilarities between transporter substrate, ion, and inhibitor binding sites. Mutations that alter the binding affinity or substrate uptake inhibition potency of inhibitors by at least 3-fold are the focus of this review. These findings are clarifying the picture regarding substrate uptake inhibitor/transporter protein interactions at the level of the drug pharmacophore and the amino acid residue, information necessary for rational design of novel medications for substance abuse and a variety of psychiatric disorders.