Modulation of triheteromeric NMDA receptors by N-terminal domain Ligands
Modulation of triheteromeric NMDA receptors by N-terminal domain Ligands
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DOI：
10.1016/j.neuron.2005.03.005
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发表时间：
2005-04-21
期刊：
影响因子：
16.2
通讯作者：
Paoletti, P
中科院分区：
文献类型：
--
作者：
Hatton, CJ;Paoletti, P
NMDA受体（NMDARs）是NR 1和NR 2（A-D）亚基的异聚体组装体，其性质受所掺入的NF 12亚基的类型的严重影响。虽然只有一种类型的NR 2亚基的NMDAR已被广泛表征，但对含有两种不同NR 2亚基的受体知之甚少，尽管有令人信服的证据表明这种三异聚体受体存在于体内。我们使用了点突变的方法，允许分离的重组三异源聚体NMDAR拥有两个不同的NF 12 N-末端结构域（NTD）。我们发现，在受体相关的NR 2A-NTD（传感纳摩尔锌）和NR 2B-NTD（传感艾芬地尔），每个NTD结合位点保留选择性高亲和力的ingand。然而，每个配体仅产生部分抑制，并且最大抑制需要两个NR 2-NTD被它们各自的配体占据。类似地，NR 1/2A/2C受体被锌以高效力但低功效抑制。因此，同源N-末端结构域之间的相互作用决定了三异聚体NIVIDAR的独特药理学性质。
NMDA receptors (NMDARs) are heteromeric assemblies of NR1 and NR2(A-D) subunits with properties heavily influenced by the type of NF12 subunit incorporated. While NMDARs with only one type of NR2 subunit have been extensively characterized, little is known about receptors containing two different NR2 subunits, despite compelling evidence that such triheteromeric receptors exist in vivo. We used a point-mutation approach that allows isolation of recombinant triheteromeric NMDARs possessing two different NF12 N-terminal domains (NTDs). We show that in receptors associating the NR2A-NTD (sensing nanomolar Zn) and the NR2B-NTD (sensing ifenprodil), each NTD binding site retains selective high affinity for its ingand. However, each ligand produces only partial inhibition, and maximal inhibition requires occupancy of both NR2-NTDs by their respective ligands. Similarly, NR1/2A/2C receptors are inhibited by zinc with high potency but low efficacy. Therefore, interactions between homologous N-terminal domains determine the unique pharmacological properties of triheteromeric NIVIDARs.