The dopamine transporter mediates uptake of dopamine into neurons and is a
major target for various pharmacologically active drugs and environmental t
oxins. Since its cloning, much information has been obtained regarding its
structure and function. Binding domains for dopamine and various blocking d
rugs including cocaine an likely formed by interactions with multiple amino
acid residues, some of which are separate in the primary structure but lie
close together in the still unknown tertiary structure. Chimera and site-d
irected mutagenesis studies suggest the involvement of both overlapping and
separate domains in the interaction with substrates and blockers, whereas
recent findings with involvement of both overlapping and separate domains i
n the interaction with substrates nad blockers, binding of blockers such as
cocaine. The dopamine transporter can also operate in reverse, i.e. in an
efflux mode, and recent mutagenesis experiments show different structural r
equirements for inward and outward transport. Strong evidence for dopamine
transporter domains selectively influencing binding of dopamine or cocaine
analogs has not yet emerged, although the development of a cocaine antagoni
st at the level of the transporter remains a possibility. (C) 2000 Elsevier
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