Dopamine Transport by the Serotonin Transporter: A Mechanistically Distinct Mode of Substrate Translocation
Year: 2011
Type: article
Abstract: 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.
Source: Journal of Neuroscience
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Awards: G1727692481, Structure and Function of Neurotransmitter Transporters, G5689301838, Molecular Studies of Catecholamine Transporters, Individual Differences in Cocaine Activation/Reward and the Dopamine Transporter, G6780540481, Cocaine Sensitization and Dopamine Transporter Regulation, MOLECULAR STUDIES OF CATECHOLAMINE TRANSPORTERS, G9000220946, G9000284358, G9000314419
OpenAlex ID: W2008973569