Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors.
Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors.
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发表时间：
1993-10
影响因子：
3.6
通讯作者：
K. Williams
中科院分区：
文献类型：
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作者：
K. Williams
非典型N-甲基-D-天冬氨酸（NMDA）受体拮抗剂艾芬地尔的影响进行了研究，电压钳记录非洲爪蟾卵母细胞表达异聚体NMDA受体克隆NR 1和NR 2亚基RNA。在-70 mV电压钳位的卵母细胞中，艾芬地尔以高亲和力抑制NR 1A/NR 2B受体的NMDA诱导电流（IC 50 = 0.34 μ M）。NR 1A/NR 2A受体对艾芬地尔的亲和力（IC 50 = 146 μ M）比NR 1A/NR 2B受体低400倍。低浓度艾芬地尔作用于NR 1A/NR 2B受体的抑制作用的起始速率显著慢于高浓度艾芬地尔作用于NR 1A/NR 2A受体的抑制作用的起始速率。艾芬地尔对NR 1A/NR 2B受体阻滞的起效和恢复无活性依赖性。低浓度艾芬地尔对NR 1A/NR 2B受体的抑制作用不具有电压依赖性。与此相反，高浓度的艾芬地尔对NR 1A/NR 2A受体的抑制作用是部分电压依赖性的，并且在超极化膜电位下比在去极化膜电位下对NMDA诱导的电流的抑制更大。在艾芬地尔的存在下，NMDA电流的逆转电位没有改变。艾芬地尔可能是NR 1A/NR 2A受体的弱开放通道阻滞剂。100 μ M艾芬地尔对NR 1A/NR 2A受体的抑制程度不因细胞外甘氨酸浓度的变化而改变。然而，1 μ M的艾芬地尔对NR 1A/NR 2B受体的抑制作用随着甘氨酸浓度的增加而减弱。因此，艾芬地尔对NR 1A/NR 2B受体的部分作用机制可能涉及甘氨酸效应的非竞争性拮抗作用。这些结果表明，艾芬地尔的作用机制，以及这种拮抗剂的效力，在非洲爪蟾卵母细胞中表达的NR 1A/NR 2B和NR 1A/NR 2A受体是不同的。
The effects of the atypical N-methyl-D-aspartate (NMDA) receptor antagonist ifenprodil were investigated by voltage-clamp recording of Xenopus oocytes expressing heteromeric NMDA receptors from cloned NR1 and NR2 subunit RNAs. In oocytes voltage-clamped at -70 mV, ifenprodil inhibited NMDA-induced currents at NR1A/NR2B receptors with high affinity (IC50 = 0.34 microM). The affinity of NR1A/NR2A receptors for ifenprodil (IC50 = 146 microM) was 400-fold lower than that of NR1A/NR2B receptors. The rate of onset of inhibition by low concentrations of ifenprodil acting at NR1A/NR2B receptors was considerably slower than the onset of inhibition seen with high concentrations of ifenprodil acting at NR1A/NR2A receptors. The onset and recovery of blockade by ifenprodil at NR1A/NR2B receptors were not activity dependent. The inhibitory effects of low concentrations of ifenprodil at NR1A/NR2B receptors were not voltage dependent. In contrast, the inhibitory effects of high concentrations of ifenprodil at NR1A/NR2A receptors were partially voltage dependent, and a greater inhibition of NMDA-induced currents was seen at hyperpolarized membrane potentials than at depolarized membrane potentials. The reversal potential of NMDA currents was not altered in the presence of ifenprodil. Ifenprodil may act as a weak open-channel blocker of NR1A/NR2A receptors. The degree of inhibition seen with 100 microM ifenprodil at NR1A/NR2A receptors was not altered by changes in the concentration of extracellular glycine. However, the inhibitory effect of 1 microM ifenprodil at NR1A/NR2B receptors was reduced by increasing the concentration of glycine. Thus, part of the mechanism of action of ifenprodil at NR1A/NR2B receptors may involve noncompetitive antagonism of the effects of glycine. These results indicate that the mechanism of action of ifenprodil, as well as the potency of this antagonist, is different at NR1A/NR2B and NR1A/NR2A receptors expressed in Xenopus oocytes.