TY - JOUR
T1 - Zinc inhibition of γ-aminobutyric acid transporter 4 (GAT4) a link between excitatory and inhibitory neurotransmission
AU - Cohen-Kfir, Einav
AU - Lee, William
AU - Eskandari, Sepehr
AU - Nelson, Nathan
PY - 2005/4/26
Y1 - 2005/4/26
N2 - γ-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 (Ki of 3 μM). 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. 2005 by The National Academy of Sciences of the USA.
AB - γ-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 (Ki of 3 μM). 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. 2005 by The National Academy of Sciences of the USA.
KW - Glutamate
KW - Synapse
KW - Transport
KW - Xenopus oocytes
UR - http://www.scopus.com/inward/record.url?scp=17844394176&partnerID=8YFLogxK
U2 - 10.1073/pnas.0501431102
DO - 10.1073/pnas.0501431102
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 15829583
AN - SCOPUS:17844394176
SN - 0027-8424
VL - 102
SP - 6154
EP - 6159
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 17
ER -