NMDA受体激活和调节的双向变构途径-动脉网

Bi-directional allosteric pathway in NMDA receptor activation and modulation

Nature 等信源发布 2024-10-13 06:28

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AbstractN-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization.

摘要N-甲基-D-天冬氨酸（NMDA）受体是参与学习和记忆的离子型谷氨酸受体。NMDA受体主要包含两个GluN1和两个GluN2亚基。GluN2亚基决定了生物物理受体的特性，包括受体激活和脱敏的程度。

GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational basis of their functional divergence, we utilize single-molecule fluorescence resonance energy transfer to probe the extracellular domains of these receptor subtypes under resting and ligand-bound conditions.

含有GluN2A和GluN2D的受体代表两个功能极端。为了揭示其功能差异的构象基础，我们利用单分子荧光共振能量转移来探测静息和配体结合条件下这些受体亚型的细胞外结构域。

We find that the conformational profile of the GluN2 amino-terminal domain correlates with the disparate functions of GluN2A- and GluN2D-containing receptors. Changes at the pre-transmembrane segments inversely correlate with those observed at the amino-terminal domain, confirming direct allosteric communication between these domains.

我们发现，GluN2氨基末端结构域的构象特征与含GluN2A和GluN2D的受体的不同功能相关。跨膜前片段的变化与氨基末端结构域观察到的变化呈负相关，证实了这些结构域之间的直接变构通讯。

Additionally, binding of a positive allosteric modulator at the transmembrane domain shifts the conformational profile of the amino-terminal domain towards the active state, revealing a bidirectional allosteric pathway between extracellular and transmembrane domains..

此外，跨膜结构域上正变构调节剂的结合将氨基末端结构域的构象转变为活性状态，揭示了细胞外和跨膜结构域之间的双向变构途径。。

IntroductionThe majority of excitatory neurotransmission in the mammalian central nervous system is accounted for by glutamatergic signaling. The ionotropic glutamate receptor family includes N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, and delta receptors1,2,3,4,5,6.

引言哺乳动物中枢神经系统中的大多数兴奋性神经传递是由谷氨酸能信号传导引起的。离子型谷氨酸受体家族包括N-甲基-D-天冬氨酸（NMDA），α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA），红藻氨酸和δ受体1,2,3,4,5,6。

NMDA receptor signaling is involved in learning, memory, and synaptic plasticity, while dysfunction of NMDA receptors has been implicated in various neurological conditions, such as epilepsy, developmental delay, and ischemic stroke7,8,9. The NMDA receptor is a ligand-gated ion channel that requires simultaneous binding of glutamate and co-agonist glycine to activate5,10,11.

NMDA受体信号传导涉及学习，记忆和突触可塑性，而NMDA受体的功能障碍与各种神经系统疾病有关，如癫痫，发育迟缓和缺血性中风7,8,9。NMDA受体是一种配体门控离子通道，需要谷氨酸和共激动剂甘氨酸同时结合才能激活5,10,11。

NMDA receptors adopt a heterotetrameric structure, with each receptor comprising two obligatory glycine-binding GluN1 subunits and two glutamate-binding GluN2 (A-D) and/or glycine-binding GluN3 (A-B) subunits3,5,12,13,14,15. These various subunit types share a conserved architecture consisting of extracellular amino-terminal (ATD) and agonist-binding domains (ABD), a transmembrane domain (TMD), and an intracellular carboxyl-terminal domain (CTD)5,12,13,16.

NMDA受体采用异四聚体结构，每个受体包含两个必需的甘氨酸结合GluN1亚基和两个谷氨酸结合GluN2（a-D）和/或甘氨酸结合GluN3（a-B）亚基3,5,12,13,14,15。这些不同的亚基类型共享由细胞外氨基末端（ATD）和激动剂结合结构域（ABD），跨膜结构域（TMD）和细胞内羧基末端结构域（CTD）5,12,13,16组成的保守结构。

The binding of glutamate and glycine to the GluN2 and GluN1 agonist-binding domains induces conformational changes throughout the receptor, forming a transmembrane ion channel pore permeable to sodium, potassium, and calcium ions.Several functional characteristics of NMDA receptors, including their extent of activation, desensitization profiles, and agonist potency, are determined by the identity of the GluN2 subunit17,18,19,20,21.

谷氨酸和甘氨酸与GluN2和GluN1激动剂结合结构域的结合诱导整个受体的构象变化，形成可渗透钠，钾和钙离子的跨膜离子通道孔。NMDA受体的几种功能特征，包括其激活程度，脱敏谱和激动剂效力，由GluN2亚基17,18,19,20,21的身份决定。

GluN2A and GluN2D subunits represent opposite ends of the functional spectrum and differ in expression patterns. GluN1/GluN2A NMDA receptors are expressed broadly throughout the cortex and hippocampus3,.

GluN2A和GluN2D亚基代表功能谱的两端，表达模式不同。GluN1/GluN2A NMDA受体广泛表达于整个皮层和海马3，。

(1)

Where IVV and IVH are the measured fluorescence intensities with the excitation polarizer vertically oriented and the emission polarizer vertically and horizontally oriented, respectively. G is the grating correction factor for the detection system. As polarization ratios did not satisfy the Anderson-Darling normality test, they were compared using non-parametric Kruskal-Wallis and Dunn’s multiple comparisons tests, which were performed using GraphPad Prism version 10.0.3 (GraphPad Software).

其中IVV和IVH分别是激发偏振片垂直取向和发射偏振片垂直和水平取向的测量荧光强度。G是检测系统的光栅校正系数。由于极化率不满足Anderson-Darling正态性检验，因此使用非参数Kruskal-Wallis和Dunn的多重比较检验对它们进行了比较，这些检验是使用GraphPad Prism版本10.0.3（GraphPad软件）进行的。

P-values < 0.05 are considered significant. The calculated polarization ratio values are provided in Supplementary Table 1. The values range from 0.07 to 0.26, and there are no significant changes in the polarization ratios between the conditions measured (apo, liganded, and modulator bound) for a given site.

P值<0.05被认为是显着的。补充表1中提供了计算出的极化比值。该值的范围为0.07至0.26，并且对于给定位点，测量的条件（载脂蛋白，配体和调制器结合）之间的极化比没有显着变化。

Thus, it is unlikely that the changes in smFRET between the different conditions (apo, liganded, and modulator bound) measured here for a given site arise due to differences in the orientation factor68.To ensure that our data acquisition and analysis were not biased, one set of data for the amino-terminal domain smFRET was obtained blind for each investigated condition.

因此，对于给定位点，此处测量的不同条件（载脂蛋白，配体和调节剂结合）之间的smFRET变化不太可能由于取向因子68的差异而产生。为了确保我们的数据采集和分析没有偏差，对于每个研究的条件，都盲目获得了一组氨基末端结构域smFRET的数据。

The samples were prepared and unidentified by one lab member and collected and analyzed by a second without knowledge of the conditions. We observed that this set was statistically similar to the data obtained without blinding.Reporting summaryFurther information on research design is available in the Nature Portfolio Reporting Summary linked to this article..

样品由一名实验室成员制备和鉴定，并在不知道条件的情况下由第二名实验室成员收集和分析。我们观察到，这组数据在统计学上与无盲法获得的数据相似。报告摘要有关研究设计的更多信息，请参阅本文链接的Nature Portfolio Reporting Summary。。

Data availability

数据可用性

The data that support this study are available from the corresponding authors upon request. Source data are provided in this paper. The structural data referred to within this study was previously published and can be accessed via the Protein Data Bank (PDB) under the following accession numbers 7EOS, 8E96.

支持这项研究的数据可应要求从通讯作者那里获得。本文提供了源数据。本研究中提到的结构数据先前已发布，可以通过蛋白质数据库（PDB）以以下登录号7EOS，8E96访问。

Source data are provided in this paper..

本文提供了源数据。。

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Download referencesAcknowledgementsThis project was supported by a training fellowship from the Gulf Coast Consortia on the Houston Area Molecular Biophysics Program (Grant No. T32 GM008280) to P.B. and National Institutes of Health Grant (R35GM122528) to V.J. The authors declare no competing financial interests.Author informationAuthors and AffiliationsThe University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USAPaula A.

下载参考文献致谢该项目得到了海湾沿岸财团对休斯顿地区分子生物物理学计划（批准号T32 GM008280）和美国国立卫生研究院对V.J.的资助（R35GM122528）的培训奖学金的支持。作者声明没有相互竞争的经济利益。作者信息作者和附属机构德克萨斯大学安德森癌症中心UTHealth Houston生物医学科学研究生院，德克萨斯州休斯顿，USAPULA A。

Bender & Vasanthi JayaramanDepartment of Biochemistry and Molecular Biology, Center for Membrane Biology, University of Texas Health Science Center at Houston, Houston, TX, USAPaula A. Bender, Subhajit Chakraborty, Ryan J. Durham, Vladimir Berka, Elisa Carrillo & Vasanthi JayaramanAuthorsPaula A. BenderView author publicationsYou can also search for this author in.

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PubMed Google ScholarContributionsP.A.B. performed the smFRET measurements, analyzed the smFRET data, and wrote and edited the manuscript. E.C. performed the electrophysiology measurements analyzed the electrophysiology data, and also assisted with cell culture. S.C. performed part of the smFRET experiments for GluN2D, and for GluN2D with GNE-9278, R.J.D.

PubMed谷歌学术贡献SP。A、 B.进行smFRET测量，分析smFRET数据，并撰写和编辑手稿。E、 C.进行电生理测量，分析电生理数据，并辅助细胞培养。S、 C.对GluN2D和带有GNE-9278的GluN2D进行了部分smFRET实验，R.J.D。

performed part of the smFRET experiments for GluN2D, and V.B. trained P.A.B. to do the smFRET experiments and performed part of the smFRET experiments and analyzed the smFRET data. V.J. designed the research, analyzed the data, and wrote and edited the manuscript.Corresponding authorCorrespondence to.

对GluN2D进行了部分smFRET实验，V.B.培训了P.A.B.进行了smFRET实验，并进行了部分smFRET实验并分析了smFRET数据。五、 J.设计了研究，分析了数据，撰写并编辑了手稿。对应作者对应。

Vasanthi Jayaraman.Ethics declarations

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Nature Communications thanks Paul Selvin, who co-reviewed with Rohit Vaidya, and the other anonymous reviewers for their contribution to the peer review of this work. A peer review file is available.

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Reprints and permissionsAbout this articleCite this articleBender, P.A., Chakraborty, S., Durham, R.J. et al. Bi-directional allosteric pathway in NMDA receptor activation and modulation.

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