Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2005 Apr 26;10217:6154-9. doi: 10.1073/pnas.0501431102.
Show Gene links
Show Anatomy links
Zinc inhibition of gamma-aminobutyric acid transporter 4 (GAT4) reveals a link between excitatory and inhibitory neurotransmission.
Cohen-Kfir E
,
Lee W
,
Eskandari S
,
Nelson N
.
???displayArticle.abstract???
gamma-Aminobutyric acid (GABA) transporters (GATs) play an important role in inhibitory neurotransmission by clearing synaptically released GABA and by maintaining low resting levels of GABA in synaptic and extrasynaptic regions. In certain brain regions, vesicular zinc is colocalized and coreleased with glutamate and modulates the behavior of a number of channels, receptors, and transporters. We examined the effect of zinc on expressed GATs (GAT1, GAT2, GAT3, and GAT4) in Xenopus laevis oocytes by using tracer flux and electrophysiological methods. We show that zinc is a potent inhibitor of GAT4 (K(i) of 3 muM). Immunolocalization of GAT4 in the hippocampus revealed dense localization in the CA1 and CA3 regions of the hippocampus, regions which are known to be heavily populated by zinc-containing glutamatergic neurons. The results suggest a physiological role of synaptically released zinc in the hippocampus, because zinc released from hyperactive glutamatergic neurons may simultaneously bring about elevated GABAergic inhibition. Therefore, this mode of zinc function signifies a link between excitatory and inhibitory neurotransmission and may play a neuroprotective role against glutamate-induced excitotoxicity.
Assaf,
Release of endogenous Zn2+ from brain tissue during activity.
, Pubmed
Assaf,
Release of endogenous Zn2+ from brain tissue during activity.
,
Pubmed
Barberis,
Zinc inhibits miniature GABAergic currents by allosteric modulation of GABAA receptor gating.
2000,
Pubmed
Beaulieu,
Enrichment of glutamate in zinc-containing terminals of the cat visual cortex.
1992,
Pubmed
Borden,
GABA transporter heterogeneity: pharmacology and cellular localization.
1996,
Pubmed
Büsselberg,
Mammalian voltage-activated calcium channel currents are blocked by Pb2+, Zn2+, and Al3+.
1994,
Pubmed
Chen,
Differential sensitivity of recombinant N-methyl-D-aspartate receptor subtypes to zinc inhibition.
1997,
Pubmed
Cole,
Seizures and neuronal damage in mice lacking vesicular zinc.
2000,
Pubmed
Cole,
Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene.
1999,
Pubmed
Conti,
GABA transporters in the mammalian cerebral cortex: localization, development and pathological implications.
2004,
Pubmed
During,
Hippocampal GABA transporter function in temporal-lobe epilepsy.
1995,
Pubmed
Feller,
Hippocampal mossy fiber zinc deficit in mice genetically selected for ethanol withdrawal seizure susceptibility.
1991,
Pubmed
Frederickson,
Neurobiology of zinc and zinc-containing neurons.
1989,
Pubmed
Frederickson,
Zinc-containing neurons.
1994,
Pubmed
Frederickson,
Synaptically released zinc: physiological functions and pathological effects.
2001,
Pubmed
Fukahori,
Zinc content in discrete hippocampal and amygdaloid areas of the epilepsy (El) mouse and normal mice.
1988,
Pubmed
Fukahori,
Effects of dietary zinc status on seizure susceptibility and hippocampal zinc content in the El (epilepsy) mouse.
1990,
Pubmed
Gadea,
Glial transporters for glutamate, glycine, and GABA: II. GABA transporters.
2001,
Pubmed
Gutiérrez,
The GABAergic phenotype of the "glutamatergic" granule cells of the dentate gyrus.
2003,
Pubmed
Henze,
The multifarious hippocampal mossy fiber pathway: a review.
2000,
Pubmed
Hosie,
Zinc-mediated inhibition of GABA(A) receptors: discrete binding sites underlie subtype specificity.
2003,
Pubmed
Howell,
Stimulation-induced uptake and release of zinc in hippocampal slices.
,
Pubmed
Ibata,
Electron microscopic demonstration of zinc in the hippocampal formation using Timm's sulfide silver technique.
1969,
Pubmed
Ju,
Zn2+ inhibits glycine transport by glycine transporter subtype 1b.
2004,
Pubmed
,
Xenbase
Jursky,
Developmental expression of GABA transporters GAT1 and GAT4 suggests involvement in brain maturation.
1996,
Pubmed
Jursky,
Developmental expression of the neurotransmitter transporter NTT4.
1999,
Pubmed
Jursky,
Developmental expression of the neurotransmitter transporter GAT3.
1999,
Pubmed
Kanner,
Ion-coupled neurotransmitter transport.
1989,
Pubmed
Lawrence,
Interneuron diversity series: containing the detonation--feedforward inhibition in the CA3 hippocampus.
2003,
Pubmed
Li,
Rapid translocation of Zn(2+) from presynaptic terminals into postsynaptic hippocampal neurons after physiological stimulation.
2001,
Pubmed
Lin,
Zinc-induced augmentation of excitatory synaptic currents and glutamate receptor responses in hippocampal CA3 neurons.
2001,
Pubmed
Liu,
Molecular characterization of four pharmacologically distinct gamma-aminobutyric acid transporters in mouse brain [corrected].
1993,
Pubmed
,
Xenbase
Loland,
Defining proximity relationships in the tertiary structure of the dopamine transporter. Identification of a conserved glutamic acid as a third coordinate in the endogenous Zn(2+)-binding site.
1999,
Pubmed
MacAulay,
Engineered Zn(2+) switches in the gamma-aminobutyric acid (GABA) transporter-1. Differential effects on GABA uptake and currents.
2001,
Pubmed
,
Xenbase
Nelson,
Cloning of the human brain GABA transporter.
1990,
Pubmed
Nelson,
The family of Na+/Cl- neurotransmitter transporters.
1998,
Pubmed
Norregaard,
Delineation of an endogenous zinc-binding site in the human dopamine transporter.
1998,
Pubmed
Paoletti,
High-affinity zinc inhibition of NMDA NR1-NR2A receptors.
1997,
Pubmed
,
Xenbase
Rassendren,
Zinc has opposite effects on NMDA and non-NMDA receptors expressed in Xenopus oocytes.
1990,
Pubmed
,
Xenbase
Roettger,
GABA and glutamate transporters: therapeutic and etiologic implications for epilepsy.
1999,
Pubmed
Ruiz,
Endogenous zinc inhibits GABA(A) receptors in a hippocampal pathway.
2004,
Pubmed
Sacher,
Presteady-state and steady-state kinetics and turnover rate of the mouse gamma-aminobutyric acid transporter (mGAT3).
2002,
Pubmed
,
Xenbase
Sawashita,
Change of zinc distribution in rat brain with increasing age.
1997,
Pubmed
Sindreu,
Boutons containing vesicular zinc define a subpopulation of synapses with low AMPAR content in rat hippocampus.
2003,
Pubmed
Sperk,
Expression of plasma membrane GABA transporters but not of the vesicular GABA transporter in dentate granule cells after kainic acid seizures.
2003,
Pubmed
Spiridon,
Modulation by zinc of the glutamate transporters in glial cells and cones isolated from the tiger salamander retina.
1998,
Pubmed
Takeda,
Differential effects of zinc on glutamatergic and GABAergic neurotransmitter systems in the hippocampus.
2004,
Pubmed
Takeda,
Movement of zinc and its functional significance in the brain.
2000,
Pubmed
Tapiero,
Trace elements in human physiology and pathology: zinc and metallothioneins.
2003,
Pubmed
Uchida,
Molecular cloning of the cDNA for an MDCK cell Na(+)- and Cl(-)-dependent taurine transporter that is regulated by hypertonicity.
1992,
Pubmed
,
Xenbase
Vandenberg,
Molecular basis for differential inhibition of glutamate transporter subtypes by zinc ions.
1998,
Pubmed
,
Xenbase
Vogt,
The actions of synaptically released zinc at hippocampal mossy fiber synapses.
2000,
Pubmed
Walker,
Monosynaptic GABAergic signaling from dentate to CA3 with a pharmacological and physiological profile typical of mossy fiber synapses.
2001,
Pubmed
Weiss,
Zn(2+): a novel ionic mediator of neural injury in brain disease.
2000,
Pubmed
Whitlow,
The anticonvulsant valproate increases the turnover rate of gamma-aminobutyric acid transporters.
2003,
Pubmed
,
Xenbase
Williamson,
Prolonged GABA responses in dentate granule cells in slices isolated from patients with temporal lobe sclerosis.
1995,
Pubmed
Xu,
Chelation of zinc by diethyldithiocarbamate facilitates bursting induced by mixed antidromic plus orthodromic activation of mossy fibers in hippocampal slices.
1993,
Pubmed