Subunit-specific roles of glycine-binding domains in activation of NR1/NR3 N-methyl-D-aspartate receptors
Subunit-specific roles of glycine-binding domains in activation of NR1/NR3 N-methyl-D-aspartate receptors
复制标题
DOI：
10.1124/mol.106.03070
复制
发表时间：
2007-01-01
影响因子：
3.6
通讯作者：
Zhang, Dongxian
中科院分区：
文献类型：
--
作者：
Awobuluyi, Marc;Yang, Jin;Zhang, Dongxian
由NR 1和NR 3亚基组成的N-甲基-D-天冬氨酸受体（NMDAR）与其他NMDAR亚型的不同之处在于它们需要单独的甘氨酸来激活。然而，很少有人知道这些受体的激活机制。使用NMDAR甘氨酸位点激动剂/拮抗剂结合NR 1和NR 3配体结合核心的功能性诱变，我们相当令人惊讶地证明，激动剂单独与NR 3结合足以激活NR 1/NR 3受体电流的重要组成部分。因此，NR 1/NR 3受体中NR 1的apo构象允许受体活化。激动剂结合的NR 1也可能有助于峰值NR 1/NR 3受体电流，但特别是使显着的NR 1/NR 3受体电流衰减在这里研究的条件下，大概是通过一个缓慢的组件脱敏。NR 1/NR 3受体的配体研究也表明NR 3和NR 1之间的不同激动剂选择性，因为一些高亲和力NR 1激动剂仅最低限度地激活NR 1/NR 3受体，而其他NR 1激动剂与甘氨酸一样有效。此外，配体NR 3亚基似乎是NR 1/NR 3受体激活中NR 1有效参与所必需的，表明两个亚基之间存在显著的相互作用。因此，NR 3亚基在亚基组装和配体结合/通道偶联方面诱导NR 1的可塑性，这在配体门控离子通道亚基中是独特的。
N-Methyl-D-aspartate receptors (NMDARs) composed of NR1 and NR3 subunits differ from other NMDAR subtypes in that they require glycine alone for activation. However, little else is known about the activation mechanism of these receptors. Using NMDAR glycine-site agonists/antagonists in conjunction with functional mutagenesis of the NR1 and NR3 ligand-binding cores, we demonstrate quite surprisingly that agonist binding to NR3 alone is sufficient to activate a significant component of NR1/NR3 receptor currents. Thus, the apo conformation of NR1 in NR1/NR3 receptors is permissive for receptor activation. Agonist-bound NR1 may also contribute to peak NR1/NR3 receptor currents but specifically enables significant NR1/NR3 receptor current decay under the conditions studied here, presumably via a slow component of desensitization. Ligand studies of NR1/NR3 receptors also suggest differential agonist selectivity between NR3 and NR1, as some high-affinity NR1 agonists only minimally activate NR1/NR3 receptors, whereas other NR1 agonists are as potent as glycine. Furthermore, liganded NR3 subunits seem necessary for effective engagement of NR1 in NR1/NR3 receptor activation, suggesting significant interactivity between the two subunits. NR3 subunits thus induce plasticity in NR1 with respect to subunit assembly and ligand binding/channel coupling that is unique among ligand-gated ion channel subunits.