A subunit-selective potentiator of NR2C-and NR2D-containing NMDA receptors
A subunit-selective potentiator of NR2C-and NR2D-containing NMDA receptors
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DOI：
10.1038/ncomms1085
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发表时间：
2010-10-01
影响因子：
16.6
通讯作者：
Traynelis, Stephen F.
中科院分区：
文献类型：
--
作者：
Mullasseril, Praseeda;Hansen, Kasper B.;Traynelis, Stephen F.
NMDA 受体是 NR1 和 NR2A-D 亚基的四聚体复合物，介导兴奋性突触传递并在神经系统疾病中发挥作用。在本文中，我们鉴定了一种包含 NR2C 或 NR2D 亚基的新型 NMDA 受体亚基选择性增强剂，它可以选择性地修饰表达 NR2C/D 亚基的区域中的电路功能。取代的四氢异喹啉 CIQ (3-氯苯基)(6,7-二甲氧基-1-((4-甲氧基苯氧基)甲基)-3,4-二氢异喹啉-2(1H)-基)甲酮) 通过增加通道开放频率而不改变谷氨酸或甘氨酸的平均开放时间或 EC50 值，将受体反应增强两倍，EC50 为 3 μM。 CIQ 的作用取决于 M1 区域 (NR2D Thr592) 中的单个残基以及 N 端结构域和激动剂结合结构域之间的接头。 CIQ 增强来自丘脑底神经元的天然含有 NR2D 的 NMDA 受体电流。我们对亚基选择性 NMDA 受体调节剂的鉴定揭示了一种新的药理学工具，可用于探究包含 NR2C 和 NR2D 的 NMDA 受体在脑功能和疾病中的作用。
NMDA receptors are tetrameric complexes of NR1 and NR2A-D subunits that mediate excitatory synaptic transmission and have a role in neurological disorders. In this article, we identify a novel subunit-selective potentiator of NMDA receptors containing the NR2C or NR2D subunit, which could allow selective modification of circuit function in regions expressing NR2C/D subunits. The substituted tetrahydroisoquinoline CIQ (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone) enhances receptor responses two-fold with an EC50 of 3 mu M by increasing channel opening frequency without altering mean open time or EC50 values for glutamate or glycine. The actions of CIQ depend on a single residue in the M1 region (NR2D Thr592) and on the linker between the N-terminal domain and agonist binding domain. CIQ potentiates native NR2D-containing NMDA receptor currents from subthalamic neurons. Our identification of a subunit-selective NMDA receptor modulator reveals a new class of pharmacological tools with which to probe the role of NR2C- and NR2D-containing NMDA receptors in brain function and disease.