PMID: 9658205Jul 11, 1998Paper

Molecular basis for differential inhibition of glutamate transporter subtypes by zinc ions

Molecular Pharmacology
R J VandenbergG A Johnston

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 microM and has no effect on glutamate transport by EAAT2 at concentrations up to 300 microM. 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 p...Continue Reading

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Citations

Feb 26, 2005·Clinical and Experimental Pharmacology & Physiology·Renae M Ryan, Robert J Vandenberg
Dec 13, 2005·Journal of Neuroscience Research·Akira MinamiAtsushi Takeda
Mar 24, 2009·The European Journal of Neuroscience·Katja RillichMichael Weick
Oct 19, 2013·Physiological Reviews·Robert J Vandenberg, Renae M Ryan
May 10, 2000·The Journal of Nutrition·R A ColvinP A Carter
May 16, 2001·The Journal of Biological Chemistry·A D MitrovicR J Vandenberg
Apr 15, 2005·Proceedings of the National Academy of Sciences of the United States of America·Einav Cohen-KfirNathan Nelson
Feb 22, 2005·Journal of Neuroscience Research·Jesús García-ColungaRicardo Miledi
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Jan 12, 2012·Toxicology and Industrial Health·Nazer MizariAhmad Reza Dehpour
Nov 9, 2017·International Journal of Molecular Sciences·Yoan Cherasse, Yoshihiro Urade
Jan 30, 2002·The Journal of Biological Chemistry·Renae M Ryan, Robert J Vandenberg
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Aug 25, 2004·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Robert J VandenbergAnn D Mitrovic

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