Insights into the mechanism and pharmacology of neurotransmitter sodium symporters

Neurotransmitter sodium symporters (NSS) belong to the SLC6 family of solute carriers and play an essential role in neurotransmitter homeostasis throughout the body. In the past decade, structural studies employing bacterial orthologs of NSSs have provided insight into the mechanism of neurotransmitter transport. While the overall architecture of SLC6 transporters is conserved among species, in comparison to the bacterial homologs, the eukaryotic SLC6 family members harbor differences in amino acid sequence and molecular structure, which underpins their functional and pharmacological diversity, as well as their ligand specificity. Here, we review the structures and mechanisms of eukaryotic NSSs, focusing on the molecular basis for ligand recognition and on transport mechanism.