Differential effects of Zn2+ on the kinetics and cocaine inhibition of dopamine transport by the human and rat dopamine transporters

Eur J Pharmacol. 2007 Jun 22;565(1-3):17-25. doi: 10.1016/j.ejphar.2007.02.027. Epub 2007 Feb 23.


Zn2+ may play a major role in the modulation of neurotransmission because it modulates membrane receptors and channels. Recent literature has shown Zn2+ inhibits dopamine transport by the dopamine transporter (DAT), the main target of cocaine and some other drugs of abuse. Cocaine inhibits DAT and modulation of the DAT by Zn2+ may alter effects of cocaine on dopamine neurotransmission. This study investigates how Zn2+ changes DAT kinetics and its inhibition by cocaine. Steady-state and pre-steady-state kinetics of DAT activity were investigated using rotating disk electrode voltammetry. Values of KM and Vmax in hDAT and effects of cocaine match those in the literature. Zn2+ allosterically inhibited transport in the human DAT (hDAT) with a KI=7.9+/-0.42 microM. Removal of endogenous Zn2+ with penicillamine in hDAT increased transport values. In contrast, Zn2+ did not alter transport by rat DAT (rDAT), with KM and Vmax values of 1.2+/-0.49 microM and 15.7+/-2.57 pmol/(sx10(6) cells), respectively, and removal of Zn2+ did not increase dopamine transport values. Zn2+ allosterically reduced the inhibition by cocaine in hDAT. Results of pre-steady-state studies demonstrated that Zn2+ increases the second order binding rate constant for dopamine to hDAT (3.5 fold to 19.2x10(6) M-1 s-1 for hDAT). In rat striatal homogenates Zn2+ increased initial dopamine transport velocity and decreased cocaine inhibition providing evidence for differences in sensitivity to Zn2+ between the three different preparations. Modulation of the DAT by Zn2+ needs to be assessed further in development of cocaine antagonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / drug effects
  • Cells, Cultured
  • Cocaine / pharmacology*
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Humans
  • Kinetics
  • Male
  • Penicillamine / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Zinc / pharmacology*


  • Dopamine Plasma Membrane Transport Proteins
  • Penicillamine
  • Cocaine
  • Zinc
  • Dopamine