The dopamine (DAT), serotonin (SERT), and norepinephrine (NET) transporters, which are collectively referred to as monoamine transporters (MATs), play significant roles in regulating the neuronal response to these neurotransmitters. MATs terminate the action of these neurotransmitters by translocating them from the synaptic space into the presynaptic neurons. These three transmitters are responsible for controlling a number of physiological, emotional, and behavioral functions, with their transporters being the site of action of drugs employed for the treatment of a variety of conditions, including depression, anxiety, ADHD, schizophrenia, and psychostimulant abuse. Provided in this unit is information on the localization and regulation of MATs and the structural components of these proteins most responsible for the translocation process. Also included is a brief description of the evolution of ligands that interact with these transporters, as well as current theories concerning the pharmacological effects of substances that interact with these sites, including the molecular mechanisms of action of uptake inhibitors and allosteric modulators. Data relating to the presence, structure, and functions of allosteric modulators are included as well. The aim of this review is to provide background information on MATs to those who are new to this field, with a focus on the therapeutic potential of compounds that interact with these substrate transport sites. © 2017 by John Wiley & Sons, Inc.

The serotonin transporter (SERT) is the principal mechanism for terminating serotonin (5-HT) signals in the nervous system and is a site of action for a variety of psychoactive drugs including antidepressants, amphetamines, and cocaine. Here we show that human SERTs (hSERTs) and rat SERTs are capable of robust dopamine (DA) uptake through a process that differs mechanistically from 5-HT transport in several unanticipated ways. DA transport by hSERT has a higher maximum velocity than 5-HT transport, requires significantly higher Na⁺and Cl⁻concentrations to sustain transport, is inhibited noncompetitively by 5-HT, and is more sensitive to SERT inhibitors, including selective serotonin reuptake inhibitors. We use a thiol-reactive methane thiosulfonate (MTS) reagent to modify a conformationally sensitive cysteine residue to demonstrate that hSERT spends more time in an outward facing conformation when transporting DA than when transporting 5-HT. Cotransfection of an inactive or an MTS-sensitive SERT with wild-type SERT subunits reveals an absence of cooperative interactions between subunits during DA but not 5-HT transport. To establish the physiological relevance of this mechanism for DA clearance, we show usingin vivohigh-speed chronoamperometry that SERT has the capacity to clear extracellularly applied DA in the hippocampal CA3 region of anesthetized rats. Together, these observations suggest the possibility that SERT serves as a DA transporterin vivoand highlight the idea that there can be distinct modes of transport of alternative physiological substrates by SERT.