Augmentation by zinc of NMDA receptor-mediated synaptic responses in CA1 of rat hippocampal slices: mediation by Src family tyrosine kinases.
Normal neuronal activity results in the release of zinc from the synaptic vesicles of glutamatergic terminals and subsequent entry into postsynaptic neurons. Although the exact physiological role of zinc translocation is currently unknown, it is very likely that intracellular zinc exerts long-term modulatory effects upon synaptic transmission since zinc affects various molecules involved in signaling pathways. In this study we used rat hippocampal slices to examine the effect of zinc on glutamatergic synaptic transmission in the Schaffer collateral-CA1 synapses. Following a 10-min exposure to 0.3-1 mM zinc, the magnitude of NMDA receptor-mediated field excitatory postsynaptic potentials (fEPSP) gradually increased over the subsequent 30-40 min. In contrast, the magnitude of AMPA/kainate receptor-mediated fEPSPs remained unchanged. The selective potentiation of NMDA receptor-mediated fEPSPs by zinc was unlikely to be a presynaptic event, since the degree of paired-pulse facilitation was unaltered. Interestingly, the specific Src family tyrosine kinase inhibitor PP2 completely blocked zinc-induced potentiation of NMDA receptor-mediated fEPSP while the inactive analog PP3 had no effect, thereby suggesting the involvement of Src family tyrosine kinases. Furthermore, zinc exposure increased levels of total and tyrosine-phosphorylated forms of NR2A and NR2B in a PP2-dependent manner in both hippocampal slices and cell cultures. In addition, zinc treatment of hippocampal cultures increased the levels of tyrosine phosphorylation at the two positive regulatory sites of Src family tyrosine kinases. Our results demonstrate that zinc increases NMDA receptor function via Src family tyrosine kinase-mediated increases of NR2A and 2B tyrosine phosphorylation. We speculate that intense release of endogenous synaptic zinc may potentiate NMDA receptor-mediated transmission in zinc-containing glutamatergic pathways by a similar mechanism.
Kim
Tae-Youn
TY
National Creative Research Initiative Center for the Study of CNS Zinc and Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
Hwang
Jung-Jin
JJ
Yun
Sung Hwan
SH
Jung
Min Whan
MW
Koh
Jae-Young
JY
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D015763:2-Amino-5-phosphonovalerate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D011720:Pyrazoles; D011743:Pyrimidines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D015032:Zinc; D019061:src-Family Kinases; C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; C121001:NR2B NMDA receptor