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Research ArticleArticle

Molecular Basis for Differential Inhibition of Glutamate Transporter Subtypes by Zinc Ions

Robert J. Vandenberg, Ann D. Mitrovic and Graham A. R. Johnston
Molecular Pharmacology July 1998, 54 (1) 189-196; DOI: https://doi.org/10.1124/mol.54.1.189
Robert J. Vandenberg
Department of Pharmacology, The University of Sydney, Sydney, New South Wales 2006, Australia
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Ann D. Mitrovic
Department of Pharmacology, The University of Sydney, Sydney, New South Wales 2006, Australia
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Graham A. R. Johnston
Department of Pharmacology, The University of Sydney, Sydney, New South Wales 2006, Australia
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Abstract

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.

Footnotes

    • Received January 16, 1998.
    • Accepted April 2, 1998.
  • Send reprint requests to: Dr. Robert Vandenberg, Department of Pharmacology, University of Sydney, Sydney, NSW, 2006, Australia. E-mail: robv{at}pharmacol.usyd.edu.au

  • This work was supported by the Australian National Health and Medical Research Council and The Ramaciotti Foundation for Medical Research.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (1)
Molecular Pharmacology
Vol. 54, Issue 1
1 Jul 1998
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Research ArticleArticle

Molecular Basis for Differential Inhibition of Glutamate Transporter Subtypes by Zinc Ions

Robert J. Vandenberg, Ann D. Mitrovic and Graham A. R. Johnston
Molecular Pharmacology July 1, 1998, 54 (1) 189-196; DOI: https://doi.org/10.1124/mol.54.1.189

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Research ArticleArticle

Molecular Basis for Differential Inhibition of Glutamate Transporter Subtypes by Zinc Ions

Robert J. Vandenberg, Ann D. Mitrovic and Graham A. R. Johnston
Molecular Pharmacology July 1, 1998, 54 (1) 189-196; DOI: https://doi.org/10.1124/mol.54.1.189
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