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Functional properties of dopamine transporter oligomers after copper linking.

  • Zhen, Juan1
  • Reith, Maarten E A1, 2
  • 1 Department of Psychiatry, New York University School of Medicine, New York, USA.
  • 2 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, USA.
Published Article
Journal of Neurochemistry
Wiley (Blackwell Publishing)
Publication Date
Nov 23, 2017
DOI: 10.1111/jnc.14259
PMID: 29168892


Although it is universally accepted that dopamine transporters (DATs) exist in monomers, dimers and tetramers (i.e. dimers of dimers), it is not known whether the oligomeric organization of DAT is a prerequisite for its ability to take up dopamine (DA), or whether each DAT protomer-the subunit of quaternary structure- functions independently in terms of DA translocation. In the present work copper phenanthroline (CuP) was used to selectively target surface DAT: increasing concentrations of CuP gradually cross-linked natural DAT dimers in LLC-PK1 cells stably expressing hDAT and thereby reduced DA uptake functionality until all surface DATs were inactivated. DATs that were not cross-linked by CuP showed normal DA uptake with DA Km at ~ 0.5 μM and DA efflux with basal and amphetamine-induced DA efflux as much as control values. The cocaine analog 2β-carbomethoxy-3β-[4-fluorophenyl]-tropane (CFT) was capable to bind to copper-cross-linked DATs, albeit with an affinity more than 5 fold decreased (Kd of CFT =109 nM after crosslinking vs 19 nM before). A kinetic analysis is offered describing the changing amounts of dimers and monomers with increasing [CuP], allowing the estimation of dimer functional activity compared with a DAT monomer. Consonant with previous conclusions for SERT and NET that only one protomer of an oligomer is active at the time, the present data indicated -a functional activity of the DAT dimer of 0.74 relative to a monomer. This article is protected by copyright. All rights reserved.

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