Conformational basis of subtype-specific allosteric control of NMDA receptor gating.
Conformational basis of subtype-specific allosteric control of NMDA receptor gating.
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NMDA 受体门控亚型特异性变构控制的构象基础。
DOI：
10.1101/2024.02.10.579740
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Isacoff,EhudY
中科院分区：
文献类型：
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作者：
Bleier,Julia;deMendonca,PhilipeRibeiroFurtado;Habrian,Chris;Stanley,Cherise;Vyklicky,Vojtech;Isacoff,EhudY
N-甲基-D-天冬氨酸受体是一种离子型谷氨酸受体，对突触传递和可塑性是不可或缺的。在具有相同GluN1亚基的异源四聚体受体中，可变的GluN2亚基设置了非常不同的功能特性，这支持了它们在神经系统中各自的生理作用。为了了解这种多样性的构象基础，我们使用单分子荧光共振能量转移(SmFRET)技术评估了不同GluN1亚基受体中共同的GluN1亚基的构象。我们在配体结合区和调节性氨基末端区域建立了smFRET传感器，以研究结构分析难以捉摸的载脂蛋白样状态和部分配基的激活中间产物。我们的结果表明，载脂蛋白和谷氨酸结合的GluN2亚基对GluN1重排具有强烈的亚型特异性影响，这表明受体活性、脱敏和激动剂效力水平高度不同的构象基础。嵌合分析揭示了导致亚型差异的结构决定因素。我们的研究为理解GluN2依赖的功能特性提供了一个框架，并可能为亚型特异性调控开辟新的途径。
N-methyl-D-aspartate receptors are ionotropic glutamate receptors that are integral to synaptic transmission and plasticity. Variable GluN2 subunits in diheterotetrameric receptors with identical GluN1 subunits set very different functional properties, which support their individual physiological roles in the nervous system. To understand the conformational basis of this diversity, we assessed the conformation of the common GluN1 subunit in receptors with different GluN2 subunits using single-molecule fluorescence resonance energy transfer (smFRET). We established smFRET sensors in the ligand binding domain and modulatory amino-terminal domain to study an apo-like state and partially liganded activation intermediates, which have been elusive to structural analysis. Our results demonstrate a strong, subtype-specific influence of apo and glutamate-bound GluN2 subunits on GluN1 rearrangements, suggesting a conformational basis for the highly divergent levels of receptor activity, desensitization and agonist potency. Chimeric analysis reveals structural determinants that contribute to the subtype differences. Our study provides a framework for understanding GluN2-dependent functional properties and could open new avenues for subtype-specific modulation.