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.

NMDA 受体 (NMDAR) 被突触释放的锌抑制。这种抑制被认为是锌通过突触间隙扩散并随后与 NMDAR 的细胞外结构域结合的结果。然而，该模型未能将观察到的高度锌敏感性 NMDAR 亚基 GluN2A 与突触后锌转运蛋白 ZnT1 结合起来，后者将细胞内锌移动到细胞外空间。在这里，我们报告细胞渗透肽对 ZnT1-GluN2A 关联的破坏强烈降低了小鼠耳蜗背核突触中突触锌对 NMDAR 的抑制作用。此外，NMDAR 的突触锌抑制需要突触后细胞内锌，这表明 ZnT1 将细胞质锌转运到靠近 NMDAR 的细胞外空间。