Chronic zinc exposure decreases the surface expression of NR2A-containing NMDA receptors in cultured hippocampal neurons.
BACKGROUND
Zinc distributes widely in the central nervous system, especially in the hippocampus, amygdala and cortex. The dynamic balance of zinc is critical for neuronal functions. Zinc modulates the activity of N-methyl-D-aspartate receptors (NMDARs) through the direct inhibition and various intracellular signaling pathways. Abnormal NMDAR activities have been implicated in the aetiology of many brain diseases. Sustained zinc accumulation in the extracellular fluid is known to link to pathological conditions. However, the mechanism linking this chronic zinc exposure and NMDAR dysfunction is poorly understood.


RESULTS
We reported that chronic zinc exposure reduced the numbers of NR1 and NR2A clusters in cultured hippocampal pyramidal neurons. Whole-cell and synaptic NR2A-mediated currents also decreased. By contrast, zinc did not affect NR2B, suggesting that chronic zinc exposure specifically influences NR2A-containg NMDARs. Surface biotinylation indicated that zinc exposure attenuated the membrane expression of NR1 and NR2A, which might arise from to the dissociation of the NR2A-PSD-95-Src complex.


CONCLUSIONS
Chronic zinc exposure perturbs the interaction of NR2A to PSD-95 and causes the disorder of NMDARs in hippocampal neurons, suggesting a novel action of zinc distinct from its acute effects on NMDAR activity.
Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
Jia
J
Zhu
Chong-Yu
CY
Shao
Wei
W
Yang
Xiao-Min
XM
Zhang
Zhen-Yong
ZY
Wu
Liang
L
Zhou
Xin-Xin
XX
Wang
Yun-Hong
YH
Li
Jun
J
Xia
Jian-Hong
JH
Luo
Ying
Y
Shen
D000679:Amygdala / Q000378:metabolism; D000818:Animals; D019921:Biotinylation; D001921:Brain / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival; D002540:Cerebral Cortex / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology / Q000379:methods; D006624:Hippocampus / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D009553:Nimodipine / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013499:Surface Properties; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology*
D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D013778:Tetrazolium Salts; D013844:Thiazoles; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D009553:Nimodipine; C022616:thiazolyl blue; D015032:Zinc