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Vol. 54, Issue 1, 189-196, July 1998
Department of Pharmacology, The University of Sydney, Sydney, New
South Wales 2006, Australia
Zinc ions (Zn2+) are stored in synaptic vesicles with
glutamate in a number of regions of the brain. When released into the synapse, Zn2+ modulates the activity of various receptors
and ion channels. Excitatory amino acid transporters (EAATs) maintain
extracellular glutamate concentrations below toxic levels and regulate
the kinetics of glutamate receptor activation. We have investigated the
actions of Zn2+ on two of the most abundant human
excitatory amino acid transporters, EAAT1 and EAAT2. Zn2+
is a noncompetitive, partial inhibitor of glutamate transport by EAAT1
with an IC50 value of 9.9 ± 2.3 µM and
has no effect on glutamate transport by EAAT2 at concentrations up to
300 µM. Glutamate and aspartate transport by EAAT1 are
associated with an uncoupled chloride conductance, but Zn2+
selectively inhibits transport and increases the relative chloride flux
through the transporter. We have investigated the molecular basis for
differential inhibition of EAAT1 and EAAT2 by Zn2+ using
site-directed mutagenesis and demonstrate that histidine residues of
EAAT1 at positions 146 and 156 form part of the Zn2+
binding site. EAAT2 contains a histidine residue at the position corresponding to histidine 146 of EAAT1, but at the position
corresponding to histidine 156 of EAAT1, EAAT2 has a glycine residue.
Mutation of this glycine residue in EAAT2 to histidine generates a
Zn2+ sensitive transporter, further confirming the role of
this residue in conferring differential Zn2+ sensitivity.
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