Differential effects of Zn2+ on the kinetics and cocaine inhibition of dopamine transport by the human and rat dopamine transporters
by
Bjorklund NL, Volz TJ, Schenk JO.
School of Molecular Biosciences, Washington State University,
Pullman, Washington 99164, USA.
Eur J Pharmacol 2007 Jun 22;565(1-3):17-25.
ABSTRACTZn2+ 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.Cocaine hotspots
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