Amine Transporters

Abstract Amine transporters in plasma membranes of nerve cells mediate the transport of dopamine, (nor)adrenaline and serotonin. These transporters are members of the larger Na + ‐ and Cl − ‐dependent neurotransmitter transporter family. All three transporters have been cloned, and the bacterial leucine transporter was the first prototypical structure available; this was followed by crystals of the drosophila dopamine transporter and the human serotonin transporter. Amine transporters are implicated in psychiatric disorders, such as attention‐deficit/hyperactivity disorder, schizophrenia, Parkinson disease, suicidal and aggressive‐impulsive behaviour, and are involved in affective disorders including depression. Amine transporters are important targets for psychostimulant drugs as well as antidepressants. Key Concepts Amine transporters in plasma membranes of nerve cells mediate the transport of dopamine, noradrenaline, adrenaline and serotonin through cotransport with Na + towards the cytosol where the Na + concentration is low. Amine uptake is best described by the alternating access model; accordingly, the transporter protein moves back and forth between outward‐ and inward‐facing conformations. Amine transporters are organised in multimeric structures, that is, oligomers consisting of varying numbers of protomers. How oligomerisation affects the function of each protomer is not fully understood. In addition to a primary central binding site for substrate and drugs, amine transporters have an extracellular vestibule, accommodating with appreciable flexibility varying small‐molecule allosteric ligands. Transporter polymorphisms and variants have been associated with increased risk for psychiatric diseases; a number of DAT variants, one‐point mutations, are known to cause parkinsonian symptoms starting at infancy in a hereditary recessive fashion. In addition to allosteric modulators, atypical inhibitors and releasers targeting amine transporters are subject of intense research.