ABSTRACT
Synaptic levels of dopamine determine the intensity of dopaminergic neuronal signaling (1); thus, clearance of dopamine from the synapse is important for maintaining neuronal homeostasis (2). The primary mechanisms for termination of synaptic transmission of dopamine are inactivation of dopamine by enzymatic degradation or diffusion from the synapse followed by selective uptake into presynaptic neurons or glial cells by the dopamine transporter (DAT) (3-8). Neurotransmitter transporters, including DAT, reaccumulate released neurotransmitter from the extracellular synapse into presynaptic terminals and vesicles, terminating the action of the neurotransmitters and recycling these signaling molecules (Fig. 1) (9). High-affinity DAT proteins maintain low intrasynaptic and extrasynaptic neurotransmitter concentrations, thus regulating synaptic efficacy (10). Mice with a genetic deletion of DAT exhibit elevated levels of dopamine and decreased rates of dopamine clearance (2). These proteins responsible for uptake are sites of action for many pharmacological agents, including drugs
of abuse, antidepressants, and neurotoxins (4, 6, 7, 11-17). Changes in DAT density and function are also implicated in neurological and psychiatric disorders, including Parkinson’s disease, schizophrenia, and addiction (6, 7, 12). Since DAT has such an important role in normal and abnormal brain function, it is necessary to examine the structure, localization, pharmacology, and regulation of this transporter protein.
