Mechanism of differential control of NMDA receptor activity by NR2 subunits.
Mechanism of differential control of NMDA receptor activity by NR2 subunits.
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DOI：
10.1038/nature07993
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发表时间：
2009-06-04
期刊：
影响因子：
64.8
通讯作者：
Paoletti, Pierre
中科院分区：
文献类型：
--
作者：
Gielen, Marc;Retchless, Beth Siegler;Mony, Laetitia;Johnson, Jon W.;Paoletti, Pierre
NMDA受体（NMDAR）是中枢神经系统中的主要类别的兴奋性神经递质受体。它们形成对钙高度渗透的谷氨酸门控离子通道，介导活动依赖性突触可塑性。NMDAR功能障碍涉及多种脑部疾病，包括中风、慢性疼痛和精神分裂症。NMDAR作为多种亚型存在，具有不同的药理学和生物物理学性质，主要由异聚体NR 1/NR 2复合物中掺入的NR 2亚基（NR 2A-NR 2D）的类型决定。NMDAR亚型之间的根本差异是它们的通道最大开放概率（Po），其跨越50倍范围，从含NR 2A的受体的~0.5到含NR 2C和NR 2D的受体的~0.01;含NR 2B的受体具有中间值（~0.1）。Po的这些差异赋予每个受体亚型独特的电荷转移能力和信号传导特性。NMDAR亚型之间活性的这种深刻差异的分子基础尚不清楚。在这里，我们证明了NMDARs的亚基特异性门控是由NR 2 N-末端结构域（NTD），细胞外蛤壳状结构域先前显示结合变构抑制剂，和连接NTD的激动剂结合结构域（ABD）的短接头形成的区域控制。NMDAR Po的亚型特异性在很大程度上反映了NR 2-NTD的开放裂隙和闭合裂隙构象之间的自发（配体非依赖性）平衡的差异。这种NTD驱动的门控控制还通过设置对内源性抑制剂锌和质子的敏感性来影响药理学特性。我们的研究结果提供了一个基于药物的双向控制NMDAR活性的概念验证，使用分子作为NR 2-NTD的“关闭器”或“开放器”，促进受体抑制或增强，分别。
NMDA receptors (NMDARs) are a major class of excitatory neurotransmitter receptors in the central nervous system. They form glutamate-gated ion channels highly permeable to calcium that mediate activity-dependent synaptic plasticity. NMDAR dysfunction is implicated in multiple brain disorders, including stroke, chronic pain and schizophrenia. NMDARs exist as multiple subtypes with distinct pharmacological and biophysical properties largely determined by the type of NR2 subunit (NR2A-NR2D) incorporated in the heteromeric NR1/NR2 complex. A fundamental difference between NMDAR subtypes is their channel maximal open probability (Po), which spans a 50-fold range from ~0.5 for NR2A-containing receptors to ~0.01 for NR2C- and NR2D-containing receptors; NR2B-containing receptors having an intermediate value (~0.1). These differences in Po confer unique charge transfer capacities and signaling properties on each receptor subtype. The molecular basis for this profound difference in activity between NMDAR subtypes is unknown. Here we demonstrate that the subunit-specific gating of NMDARs is controlled by the region formed by the NR2 N-terminal domain (NTD), an extracellular clamshell-like domain previously shown to bind allosteric inhibitors, and the short linker connecting the NTD to the agonist-binding domain (ABD). Subtype specificity of NMDAR Po largely reflects differences in the spontaneous (ligand-independent) equilibrium between open-cleft and closed-cleft conformations of the NR2-NTD. This NTD-driven gating control also impacts pharmacological properties, by setting the sensitivity to the endogenous inhibitors zinc and protons. Our results provide a proof-of-concept for a drug-based bidirectional control of NMDAR activity using molecules acting either as NR2-NTD “closers” or “openers” promoting receptor inhibition or potentiation, respectively.
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