![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
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.
This article has been cited by other articles:
|
|
 |
|
  E. Cohen-Kfir, W. Lee, S. Eskandari, and N. Nelson Zinc inhibition of {gamma}-aminobutyric acid transporter 4 (GAT4) reveals a link between excitatory and inhibitory neurotransmission PNAS, April 26, 2005; 102(17): 6154 - 6159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ju, K. R. Aubrey, and R. J. Vandenberg Zn2+ Inhibits Glycine Transport by Glycine Transporter Subtype 1b J. Biol. Chem., May 28, 2004; 279(22): 22983 - 22991. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ruiz, M. C. Walker, R. Fabian-Fine, and D. M. Kullmann Endogenous Zinc Inhibits GABAA Receptors in a Hippocampal Pathway J Neurophysiol, February 1, 2004; 91(2): 1091 - 1096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Holst, C. E. Elling, and T. W. Schwartz Metal Ion-mediated Agonism and Agonist Enhancement in Melanocortin MC1 and MC4 Receptors J. Biol. Chem., November 27, 2002; 277(49): 47662 - 47670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Scholze, L. Norregaard, E. A. Singer, M. Freissmuth, U. Gether, and H. H. Sitte The Role of Zinc Ions in Reverse Transport Mediated by Monoamine Transporters J. Biol. Chem., June 7, 2002; 277(24): 21505 - 21513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Ryan and R. J. Vandenberg Distinct Conformational States Mediate the Transport and Anion Channel Properties of the Glutamate Transporter EAAT-1 J. Biol. Chem., April 12, 2002; 277(16): 13494 - 13500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Borre, M. P. Kavanaugh, and B. I. Kanner Dynamic Equilibrium between Coupled and Uncoupled Modes of a Neuronal Glutamate Transporter J. Biol. Chem., April 12, 2002; 277(16): 13501 - 13507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Lin, A. S. Cohen, and D. A. Coulter Zinc-Induced Augmentation of Excitatory Synaptic Currents and Glutamate Receptor Responses in Hippocampal CA3 Neurons J Neurophysiol, March 1, 2001; 85(3): 1185 - 1196. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Frederickson, S. W. Suh, D. Silva, C. J. Frederickson, and R. B. Thompson Importance of Zinc in the Central Nervous System: The Zinc-Containing Neuron J. Nutr., May 1, 2000; 130(5): 1471S - 1483. [Abstract] [Full Text]
|
|
|
|
|
|
R. A. Colvin, N. Davis, R. W. Nipper, and P. A. Carter Zinc Transport in the Brain: Routes of Zinc Influx and Efflux in Neurons J. Nutr., May 1, 2000; 130(5): 1484S - 1487. [Abstract] [Full Text]
|
|
|
|
|
|
C. J. Loland, L. Norregaard, and U. Gether Defining Proximity Relationships in the Tertiary Structure of the Dopamine Transporter. IDENTIFICATION OF A CONSERVED GLUTAMIC ACID AS A THIRD COORDINATE IN THE ENDOGENOUS Zn2+-BINDING SITE J. Biol. Chem., December 24, 1999; 274(52): 36928 - 36934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Duan, C. M. Anderson, B. A. Stein, and R. A. Swanson Glutamate Induces Rapid Upregulation of Astrocyte Glutamate Transport and Cell-Surface Expression of GLAST J. Neurosci., December 1, 1999; 19(23): 10193 - 10200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Swanson and S. Duan Regulation of Glutamate Transporter Function Neuroscientist, September 1, 1999; 5(5): 280 - 282. [Abstract] [PDF]
|
|
|
|
 |
|
 D. J. Slotboom, W. N. Konings, and J. S. Lolkema Structural Features of the Glutamate Transporter Family Microbiol. Mol. Biol. Rev., June 1, 1999; 63(2): 293 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Trotti, M. Aoki, P. Pasinelli, U. V. Berger, N. C. Danbolt, R. H. Brown Jr., and M. A. Hediger Amyotrophic Lateral Sclerosis-linked Glutamate Transporter Mutant Has Impaired Glutamate Clearance Capacity J. Biol. Chem., January 5, 2001; 276(1): 576 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Mitrovic, F. Plesko, and R. J. Vandenberg Zn2+ Inhibits the Anion Conductance of the Glutamate Transporter EAAT4 J. Biol. Chem., July 6, 2001; 276(28): 26071 - 26076. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
