Contribution of the M1 Transmembrane Helix and Pre-M1 Region to Positive Allosteric Modulation and Gating of N-Methyl-D-Aspartate Receptors
Contribution of the M1 Transmembrane Helix and Pre-M1 Region to Positive Allosteric Modulation and Gating of N-Methyl-D-Aspartate Receptors
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DOI：
10.1124/mol.113.085209
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发表时间：
2013-05-01
影响因子：
3.6
通讯作者：
Traynelis, Stephen F.
中科院分区：
文献类型：
--
作者：
Ogden, Kevin K.;Traynelis, Stephen F.
N-甲基-D-天冬氨酸（NMDA）受体是谷氨酸门控离子通道，其功能对于脑中的正常兴奋性突触传递是关键的，并且其功能障碍与几种神经系统病症有关。NMDA受体功能受到内源性化合物和外源性小分子的广泛变构调节。阐明变构调节剂控制门控的结构决定因素和作用机制将增强我们对NMDA受体激活的理解，并促进新疗法的开发。在这里，我们研究了（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（CIQ）的结构决定因素，CIQ是一种GluN 2C/2D选择性正向变构调节剂。我们表明，CIQ不结合到NMDA受体的氨基末端结构域，并且不与作用于激动剂结合结构域二聚体界面或离子通道孔的调节剂共享结构决定因素。相反，我们确定了CIQ调制的关键决定因素，在该地区附近的第一个跨膜螺旋的GluN 2D，包括在一个假定的前M1袖口螺旋，可能会影响通道门控。我们还表明，突变内的GluN 2D前M1区改变开放的概率的NMDA受体。这些结果表明，一个新的网站的行动，为增强NMDA受体的小分子和牵连的前M1区的NMDA受体门控。
N-methyl-D-aspartate (NMDA) receptors are glutamate-gated ion channels whose function is critical for normal excitatory synaptic transmission in the brain and whose dysfunction has been implicated in several neurologic conditions. NMDA receptor function is subject to extensive allosteric regulation both by endogenous compounds and by exogenous small molecules. Elucidating the structural determinants and mechanism of action by which allosteric regulators control gating will enhance our understanding of NMDA receptor activation and facilitate the development of novel therapeutics. Here, we investigated the structural determinants for (3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ), a GluN2C/2D-selective positive allosteric modulator. We show that CIQ does not bind to the amino-terminal domain of the NMDA receptor and does not share structural determinants with modulators acting at the agonist-binding domain dimer interface or ion channel pore. Rather, we identified critical determinants of CIQ modulation in the region near the first transmembrane helix of GluN2D, including in a putative pre-M1 cuff helix that may influence channel gating. We also show that mutations within the GluN2D pre-M1 region alter open probability of the NMDA receptor. These results suggest a novel site of action for potentiation of NMDA receptors by small molecules and implicate the pre-M1 region in NMDA receptor gating.