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The Journal of biological chemistry v.292 no.4, 2017년, pp.1302 - 1309   SCI SCIE
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Dopamine Transporter Amino and Carboxyl Termini Synergistically Contribute to Substrate and Inhibitor Affinities

Sweeney, Carolyn G. (From the Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604 and ); Tremblay, Bradford P. (From the Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604 and ); Stockner, Thomas (the Institute for Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria ); Sitte, Harald H. (the Institute for Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria ); Melikian, Haley E. (From the Brudnick Neuropsychiatric Research Institute, Department of Psychiatry, University of Massachusetts Medical School, Worcester, Massachusetts 01604 and );
  • 초록  

    Extracellular dopamine and serotonin concentrations are determined by the presynaptic dopamine (DAT) and serotonin (SERT) transporters, respectively. Numerous studies have investigated the DAT and SERT structural elements contributing to inhibitor and substrate binding. To date, crystallographic studies have focused on conserved transmembrane domains, where multiple substrate binding and translocation features are conserved. However, it is unknown what, if any, role the highly divergent intracellular N and C termini contribute to these processes. Here, we used chimeric proteins to test whether DAT and SERT N and C termini contribute to transporter substrate and inhibitor affinities. Replacing the DAT N terminus with that of SERT had no effect on DA transport V max but significantly decreased DAT substrate affinities for DA and amphetamine. Similar losses in uptake inhibition were observed for small DAT inhibitors, whereas substituting the DAT C terminus with that of SERT affected neither substrate nor inhibitor affinities. In contrast, the N-terminal substitution was completely tolerated by the larger DAT inhibitors, which exhibited no loss in apparent affinity. Remarkably, all affinity losses were rescued in DAT chimeras encoding both SERT N and C termini. The sensitivity to amino-terminal substitution was specific for DAT, because replacing the SERT N and/or C termini affected neither substrate nor inhibitor affinities. Taken together, these findings provide compelling experimental evidence that DAT N and C termini synergistically contribute to substrate and inhibitor affinities.


  • 주제어

    dopamine transporter .   kinetics .   monoamine transporter .   selective serotonin reuptake inhibitor (SSRI) .   serotonin transporter .   amphetamine .   cocaine .   psychostimulants .   reuptake.  

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