Hollmann M, Boulter J, Maron C, Beasley L, Sullivan J, Pecht G, Heinemann S
Molecular Neurobiology Laboratory, Salk Institute, La Jolla, California 92037.
Neuron. 1993 May;10(5):943-54. doi: 10.1016/0896-6273(93)90209-a.
We have determined the gene structure for the NMDA receptor subunit gene NMDAR1. We found eight splice variants that arise from different combinations of a single 5' terminal exon insertion and three different 3' terminal exon deletions, relative to NMDAR1. We analyzed the modulation by Zn2+ of currents through homomeric receptors assembled from these splice variants and found that, in addition to its well-known inhibitory effect at high concentrations, Zn2+ potentiates agonist-induced currents at submicromolar concentrations (EC50 = 0.50 microM). This potentiation is observed only with a subset of NMDAR1 splice variants that show additional differences in pharmacological properties. Zn2+ potentiation is rapidly reversible, noncompetitive with either glutamate or glycine, and voltage independent. Zn2+ potentiation is mimicked by Cd2+, Cu2+, and Ni2+, but not by Mn2+, Co2+, Fe3+, Sn2+, or Hg2+. Our results suggest a possible role for Zn2+ as a positive modulator of NMDA receptors in certain regions of the brain.
我们已经确定了NMDA受体亚基基因NMDAR1的基因结构。相对于NMDAR1，我们发现了8种剪接变体，它们源于单个5'末端外显子插入和3种不同的3'末端外显子缺失的不同组合。我们分析了由这些剪接变体组装而成的同聚受体电流受Zn2+的调节情况，发现除了其在高浓度时众所周知的抑制作用外，Zn2+在亚微摩尔浓度（EC50 = 0.50 microM）时可增强激动剂诱导的电流。仅在显示出药理学特性上存在其他差异的一部分NMDAR1剪接变体中观察到这种增强作用。Zn2+增强作用是快速可逆的，对谷氨酸或甘氨酸均无竞争性，且与电压无关。Cd2+、Cu2+和Ni2+可模拟Zn2+的增强作用，但Mn2+、Co2+、Fe3+、Sn2+或Hg2+则不能。我们的结果表明，Zn2+在大脑某些区域可能作为NMDA受体的正向调节剂发挥作用。
