PT - JOURNAL ARTICLE AU - Mads Breum Larsen AU - Mark S. Sonders AU - Ole Valente Mortensen AU - Gaynor A. Larson AU - Nancy R. Zahniser AU - Susan G. Amara TI - Dopamine Transport by the Serotonin Transporter: A Mechanistically Distinct Mode of Substrate Translocation AID - 10.1523/JNEUROSCI.0576-11.2011 DP - 2011 Apr 27 TA - The Journal of Neuroscience PG - 6605--6615 VI - 31 IP - 17 4099 - http://www.jneurosci.org/content/31/17/6605.short 4100 - http://www.jneurosci.org/content/31/17/6605.full SO - J. Neurosci.2011 Apr 27; 31 AB - 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 using in vivo high-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 transporter in vivo and highlight the idea that there can be distinct modes of transport of alternative physiological substrates by SERT.