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J. Biol. Chem., Vol. 277, Issue 24, 21505-21513, June 14, 2002
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From the The human dopamine transporter (hDAT) contains an
endogenous high affinity Zn2+ binding site with three
coordinating residues on its extracellular face (His193,
His375, and Glu396). Upon binding to
this site, Zn2+ causes inhibition of
[3H]1-methyl-4-phenylpyridinium
([3H]MPP+) uptake. We investigated the effect
of Zn2+ on outward transport by superfusing hDAT-expressing
HEK-293 cells preloaded with [3H]MPP+.
Although Zn2+ inhibited uptake, Zn2+
facilitated [3H]MPP+ release induced by
amphetamine, MPP+, or K+-induced depolarization
specifically at hDAT but not at the human serotonin and the
norepinephrine transporter (hNET). Mutation of the Zn2+
coordinating residue His193 to Lys (the corresponding
residue in hNET) eliminated the effect of Zn2+ on efflux.
Conversely, the reciprocal mutation (K189H) conferred Zn2+
sensitivity to hNET. The intracellular
[3H]MPP+ concentration was varied to generate
saturation isotherms; these showed that Zn2+ increased
Vmax for efflux (rather than
KM-Efflux-intracellular). Thus, blockage of inward
transport by Zn2+ is not due to a simple inhibition of the
transporter turnover rate. The observations provide evidence against
the model of facilitated exchange-diffusion and support the concept
that inward and outward transport represent discrete operational modes
of the transporter. In addition, they indicate a physiological role of
Zn2+, because Zn2+ also facilitated transport
reversal of DAT in rat striatal slices.
The Role of Zinc Ions in Reverse Transport Mediated by Monoamine
Transporters*
,,,¶
Institute of Pharmacology, University of
Vienna, Währingerstrasse 13a, A-1090 Vienna, Austria and the
§ Molecular Neuropharmacology Group, Department of
Pharmacology, The Panum Institute, University of Copenhagen, DK-2200
Copenhagen N, Denmark
*
This work was supported by the Austrian Science Foundation
(Grant P-14509 to H. H. S, Grant P-15034 to M. F.), by the Danish Natural Science Research Council, by National Institutes of Health Grant P01-DA-12408, by the Lundbeck Foundation, and by the NOVO Nordisk Foundation (to U. G.).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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