Omelchenko I A, Nelson C S, Marino J L, Allen C N
Center for Research on Environmental and Occupational Toxicology, Oregon Health Sciences University, Portland, USA.
J Pharmacol Exp Ther. 1996 Jul;278(1):15-20.
Pb+2 is a potent inhibitor of N-methyl-D-aspartate (NMDA) receptors and its action is dependent on neuronal maturation. Developmentally regulated expression of NMDA receptor subunits may underlie the changing sensitivity to Pb+2. In oocytes expressing in vitro transcribed cRNAs for zeta 1 epsilon 1 or zeta 1 epsilon 2 NMDA receptor subunits, Pb+2 inhibited glutamate-activated currents with IC50 values of 0.87 +/- 0.25 and 1.21 +/- 0.22 microM, respectively, and NMDA-activated currents with IC50 values of 1.37 +/- 0.47 and 1.11 +/- 0.33 microM, respectively. In oocytes expressing zeta 1 epsilon 1 epsilon 2 subunits, the IC50 values for Pb+2 blockade of NMDA- or glutamate-activated currents were significantly larger when compared to zeta 1 epsilon 1 or zeta 1 epsilon 2 combinations. Pb+2 concentrations greater than 1 microM inhibited glutamate-activated currents with an IC50 of 6.1 +/- 1.22 microM and NMDA-activated currents with an IC50 of 6.64 +/- 3.34 microM. Pb+2 reduced the maximal current amplitude consistent with a noncompetitive block. zeta 1 epsilon 1 epsilon 2 NMDA receptors were potentiated by low concentrations of Pb+2 ( < 1.0 microM). These data suggest that brain regions with zeta 1 epsilon 1 or zeta 1 epsilon 2 NMDA receptors subunits would be more vulnerable to Pb+2 toxicity than those with zeta 1 epsilon 1 epsilon 2 NMDA-receptors, which are expressed later in development. These data provide a mechanism for the reported changes in the efficacy of block of NMDA receptors by Pb+2 during development.
铅离子（Pb²⁺）是N-甲基-D-天冬氨酸（NMDA）受体的强效抑制剂，其作用取决于神经元的成熟度。NMDA受体亚基的发育调控表达可能是对Pb²⁺敏感性变化的基础。在表达体外转录的ζ1ε1或ζ1ε2 NMDA受体亚基的cRNA的卵母细胞中，Pb²⁺抑制谷氨酸激活电流的IC50值分别为0.87±0.25和1.21±0.22微摩尔，抑制NMDA激活电流的IC50值分别为1.37±0.47和1.11±0.33微摩尔。在表达ζ1ε1ε2亚基的卵母细胞中，与ζ1ε1或ζ1ε2组合相比，Pb²⁺阻断NMDA或谷氨酸激活电流的IC50值显著更大。大于1微摩尔的Pb²⁺浓度抑制谷氨酸激活电流的IC50为6.1±1.22微摩尔，抑制NMDA激活电流的IC50为6.64±3.34微摩尔。Pb²⁺降低了最大电流幅度，符合非竞争性阻断。低浓度的Pb²⁺（<1.0微摩尔）增强了ζ1ε1ε2 NMDA受体。这些数据表明，与发育后期表达的ζ1ε1ε2 NMDA受体相比，具有ζ1ε1或ζ1ε2 NMDA受体亚基的脑区对Pb²⁺毒性更敏感。这些数据为发育过程中Pb²⁺阻断NMDA受体效能变化的报道提供了一种机制。
