The neurotransmitter transporters belonging to the solute carrier 6 (SLC6) family, including the γ-aminobutyric acid (GAT),
norepinephrine (NET), serotonin (SERT) and dopamine (DAT) transporters are extremely important drug targets of great clinical
relevance. These Na+, Cl−-dependent transporters primarily function following neurotransmission to reset neuronal signaling by transporting neurotransmitter
out of the synapse and back into the pre-synaptic neuron. Recent studies have tracked down an elusive binding site for Cl− that facilitates neurotransmitter transport using structural differences evident with bacterial family members (e.g., the
Aquifex aeolicus leucine transporter LeuTAa) that lack Cl− dependence. Additionally, the crystal structures of antidepressant-bound LeuTAa reveals a surprising mode of drug interaction that may have relevance for medication development. The study of sequence and
structural divergence between LeuTAa and human SLC6 family transporters can thus inform us as to how and why neurotransmitter transporters evolved a reliance
on extracellular Cl− to propel the transport cycle; what residue changes and helical rearrangements give rise to recognition of different substrates;
and how drugs such as antidepressants, cocaine, and amphetamines halt (or reverse) the transport process.
