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Bound to Be Different: Neurotransmitter Transporters Meet Their Bacterial Cousins

¹ Departments of Pharmacology,
² Chemistry and
³ Psychiatry Centers for
⁴ Molecular Neuroscience and
⁵ Structural Biology, Vanderbilt University Nashville, TN 37232-8548

SUMMARY

The neurotransmitter transporters belonging to the solute carrier 6 (SLC6) family, including the -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 LeuT_Aa) that lack Cl^– dependence. Additionally, the crystal structures of antidepressant-bound LeuT_Aa reveals a surprising mode of drug interaction that may have relevance for medication development. The study of sequence and structural divergence between LeuT_Aa 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.