Ifenprodil Effects on GluN2B-Containing Glutamate Receptors
Ifenprodil Effects on GluN2B-Containing Glutamate Receptors
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DOI：
10.1124/mol.112.078998
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发表时间：
2012-12-01
影响因子：
3.6
通讯作者：
Popescu, Gabriela K.
中科院分区：
文献类型：
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作者：
Amico-Ruvio, Stacy A.;Paganelli, Meaghan A.;Popescu, Gabriela K.
N-甲基-D-天冬氨酸（NMDA）受体是谷氨酸和甘氨酸门控通道，介导中枢神经系统中的快速兴奋性传递，对突触发育、可塑性和整合至关重要。它们具有丰富的调节位点，代表重要的药理学靶点。艾芬地尔是一种耐受性良好的NMDA受体抑制剂;它对含GluN 2B的受体具有选择性，并具有神经保护作用。艾芬地尔抑制NMDA受体反应的机制尚不完全清楚。这种抑制作用是不完全的，并且与其他已知的NMDA受体激动剂或调节剂是非竞争性的，尽管已经报道了艾芬地尔效力与细胞外配体（包括谷氨酸、甘氨酸、锌、质子和多胺）效力之间的相互作用。最近的结构研究表明，艾芬地尔结合到GluN 1和GluN 2B亚基的胞外N末端之间的界面处的独特位点，支持与其他胞外调节剂的相互作用是间接的观点。在这项研究中，我们研究了艾芬地尔如何影响NMDA受体的门控反应的条件下，旨在尽量减少同期配体的行动。我们发现，艾芬地尔降低NMDA受体的平衡开放概率，提高了激活的能量障碍，也偏向于低开放概率门控模式的受体。这些结果证明了艾芬地尔对NMDA受体稳态门控动力学的内在影响，并提供了预测艾芬地尔在确定的生理和病理情况下将如何影响受体反应的手段。
N-Methyl-D-aspartate (NMDA) receptors are glutamate- and glycine-gated channels that mediate fast excitatory transmission in the central nervous system and are critical to synaptic development, plasticity, and integration. They have a rich complement of modulatory sites, which represent important pharmacological targets. Ifenprodil is a well tolerated NMDA receptor inhibitor; it is selective for GluN2B-containing receptors and has neuroprotective effects. The mechanism by which ifenprodil inhibits NMDA receptor responses is not fully understood. The inhibition is incomplete and noncompetitive with other known NMDA receptor agonists or modulators, although reciprocal effects have been reported between ifenprodil potency and that of extracellular ligands including glutamate, glycine, zinc, protons, and polyamines. Recent structural studies revealed that ifenprodil binds to a unique site at the interface between the extracellular N termini of GluN1 and GluN2B sub-units, supporting the view that interactions with other extracellular modulators are indirect. In this study, we examined how ifenprodil affects the gating reaction of NMDA receptors in conditions designed to minimize actions by contemporaneous ligands. We found that ifenprodil decreased NMDA receptor equilibrium open probability by raising an energetic barrier to activation and also by biasing the receptor toward low open probability gating modes. These results demonstrate intrinsic effects of ifenprodil on NMDA receptor stationary gating kinetics and provide means to anticipate how ifenprodil will affect receptor responses in defined physiological and pathological circumstances.