突触锌对N-甲基-D-天冬氨酸受体的抑制作用取决于谷氨酸受体亚基2A（GluN2A）与锌转运体1（ZnT1）的结合。
Synaptic zinc inhibition of NMDA receptors depends on the association of GluN2A with the zinc transporter ZnT1.
作者信息
Krall Rebecca F, Moutal Aubin, Phillips Matthew B, Asraf Hila, Johnson Jon W, Khanna Rajesh, Hershfinkel Michal, Aizenman Elias, Tzounopoulos Thanos
机构信息
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Pittsburgh Hearing Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
出版信息
Sci Adv. 2020 Jul 3;6(27). doi: 10.1126/sciadv.abb1515. Print 2020 Jul.
The NMDA receptor (NMDAR) is inhibited by synaptically released zinc. This inhibition is thought to be the result of zinc diffusion across the synaptic cleft and subsequent binding to the extracellular domain of the NMDAR. However, this model fails to incorporate the observed association of the highly zinc-sensitive NMDAR subunit GluN2A with the postsynaptic zinc transporter ZnT1, which moves intracellular zinc to the extracellular space. Here, we report that disruption of ZnT1-GluN2A association by a cell-permeant peptide strongly reduced NMDAR inhibition by synaptic zinc in mouse dorsal cochlear nucleus synapses. Moreover, synaptic zinc inhibition of NMDARs required postsynaptic intracellular zinc, suggesting that cytoplasmic zinc is transported by ZnT1 to the extracellular space in close proximity to the NMDAR. These results challenge a decades-old dogma on how zinc inhibits synaptic NMDARs and demonstrate that presynaptic release and a postsynaptic transporter organize zinc into distinct microdomains to modulate NMDAR neurotransmission.
N-甲基-D-天冬氨酸受体（NMDAR）受到突触释放的锌的抑制。这种抑制作用被认为是锌扩散穿过突触间隙并随后与NMDAR的细胞外结构域结合的结果。然而，该模型未能纳入观察到的高度锌敏感的NMDAR亚基GluN2A与突触后锌转运体ZnT1的关联，ZnT1可将细胞内锌转运到细胞外空间。在此，我们报告，一种可穿透细胞的肽破坏ZnT1-GluN2A的关联，会强烈降低小鼠耳蜗背侧核突触中突触锌对NMDAR的抑制作用。此外，NMDAR的突触锌抑制作用需要突触后细胞内锌，这表明细胞质锌由ZnT1转运到紧邻NMDAR的细胞外空间。这些结果挑战了几十年来关于锌如何抑制突触NMDAR的教条，并证明突触前释放和突触后转运体将锌组织成不同的微区，以调节NMDAR神经传递。
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