预约演示

更新于：2025-05-07

GRIN2C

更新于：2025-05-07

基本信息

别名

GluN2C、Glutamate [NMDA] receptor subunit epsilon-3、glutamate ionotropic receptor NMDA type subunit 2C

+ [6]

简介

Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+) (PubMed:26875626, PubMed:36309015). Participates in synaptic plasticity for learning and memory formation by contributing to the slow phase of excitatory postsynaptic current and long-term synaptic potentiation (By similarity). Channel activation requires binding of the neurotransmitter L-glutamate to the GluN2 subunit, glycine or D-serine binding to the GluN1 subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:26875626, PubMed:36309015). NMDARs mediate simultaneously the potasium efflux and the influx of calcium and sodium (By similarity). Each GluN2 subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, Ca2(+) permeability, and binding to allosteric modulators (PubMed:26875626).

关联

项与 GRIN2C 相关的药物

(S)-(-)-DQP-997-74

靶点

GRIN2C x GRIN2D

作用机制

GRIN2C modulators [+1]

在研机构

Emory University

原研机构

Emory University

在研适应症

神经系统疾病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

NMDA receptor agonists(Shandong University)

靶点

GRIN2C x GluN1

作用机制

GRIN2C agonists [+1]

在研机构

山东大学

原研机构

山东大学

在研适应症

神经系统疾病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

DQP-26

靶点

GRIN2C x GRIN2D

作用机制

GRIN2C 抑制剂 [+1]

在研机构

Emory University

原研机构

Emory University

在研适应症

神经系统疾病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 GRIN2C 相关的临床结果

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100 项与 GRIN2C 相关的转化医学

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0 项与 GRIN2C 相关的专利（医药）

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196

项与 GRIN2C 相关的文献（医药）

2025-03-01·Journal of Pharmacological Sciences

Involvement of N-methyl-D-aspartate receptor GluN2C/GluN2D subunits in social behavior impairments in mice exposed to social defeat stress as juveniles

Article

作者: Noda, Yukihiro ; Yoshida, Mikio ; Suzuki, Chiharu ; Yoshimi, Akira ; Katada, Hikari ; Isozumi, Yuya ; Ozaki, Norio

Glutamatergic system dysfunction is associated with the pathophysiology of stress-related psychiatric disorders. However, the role of N-methyl-D-aspartate (NMDA) receptor GluN2C and GluN2D subunits in the pathophysiology of adverse juvenile experiences remain unclear. This study aimed to investigate the involvement of GluN2C and GluN2D subunits in social behavior impairments in mice exposed to social defeat stress as juveniles. Acute administration of PPDA, a GluN2C/GluN2D antagonist, and ketamine, a non-competitive NMDA receptor antagonist, attenuated social behavior impairments in stressed mice. This attenuating effect of ketamine was partially inhibited by the administration of CIQ, a GluN2C/GluN2D-containing NMDA potentiator. The prefrontal cortex of stressed mice exhibited significantly elevated levels of GluN2C and GluN2D proteins compared to control mice. These findings suggest that activation of GluN2C- and/or GluN2D-containing NMDA receptors contributes to the development of social behavioral impairments induced by juvenile social defeat stress. Moreover, these subunits may play a role in the therapeutic effects of ketamine. Targeting GluN2C/GluN2D subunits of NMDA receptors may be novel therapeutic strategies for stress-related psychiatric disorders in adolescents with adverse juvenile experiences.

2025-03-01·Journal of Neurochemistry

Input‐Specific Localization of NMDA Receptor GluN2 Subunits in Thalamocortical Neurons

Article

作者: Gilmore, Brian L. ; Swanger, Sharon A. ; Pozo‐Aranda, Aaron E. ; Wagner, Gwen N. ; Topolski, Mackenzie A. ; Studtmann, Carleigh ; Michniak, Juliana A. ; Khondaker, Rabeya ; Farris, Shannon ; Chen, Yang

ABSTRACTMolecular and functional diversity among synapses is generated, in part, by differential expression of neurotransmitter receptors and their associated protein complexes. N‐methyl‐D‐aspartate receptors (NMDARs) are tetrameric ionotropic glutamate receptors that most often comprise two GluN1 and two GluN2 subunits. NMDARs generate functionally diverse synapses across neuron populations through cell‐type‐specific expression patterns of GluN2 subunits (GluN2A–2D), which have vastly different functional properties and distinct downstream signaling. Diverse NMDAR function has also been observed at anatomically distinct inputs to a single neuron population. However, the mechanisms that generate input‐specific NMDAR function remain unknown, as few studies have investigated subcellular GluN2 subunit localization in native brain tissue. We investigated NMDAR synaptic localization in thalamocortical (TC) neurons expressing all four GluN2 subunits. Utilizing high‐resolution fluorescence imaging and knockout‐validated antibodies, we revealed subtype‐ and input‐specific GluN2 localization at corticothalamic (CT) versus sensory inputs to TC neurons in 4‐week‐old male and female C57Bl/6J mice. GluN2B was the most abundant postsynaptic subunit across all glutamatergic synapses, followed by GluN2A and GluN2C, and GluN2D was localized to the fewest synapses. GluN2B was preferentially localized to CT synapses over sensory synapses, while GluN2A and GluN2C were more abundant at sensory inputs compared to CT inputs. Furthermore, postsynaptic scaffolding proteins PSD‐95 and SAP102 were preferentially colocalized with specific GluN2 subunits, and SAP102 was more abundant at sensory synapses than PSD‐95. This work indicates that TC neurons exhibit subtype‐ and input‐specific localization of diverse NMDARs and associated scaffolding proteins that likely contribute to functional differences between CT and sensory synapses.

image

2025-02-13·Journal of Medicinal Chemistry

Design of (R)-3-(5-Thienyl)carboxamido-2-aminopropanoic Acid Derivatives as Novel NMDA Receptor Glycine Site Agonists: Variation in Molecular Geometry to Improve Potency and Augment GluN2 Subunit-Specific Activity

Article

作者: Gao, Zhen ; Schultz, Eric P. ; Yi, Feng ; Zhao, Fabao ; Lotti, James S. ; Layeux, Michael S. ; Mariottini, Sofia ; Atxabal, Unai ; Woodahl, Erica L. ; Zhang, Zhucheng ; Bunch, Lennart ; Jiang, Liyang ; Anderson, Carly M. ; Liu, Na ; Cornelison, Lauren E. ; Currier, Chandler ; Clausen, Rasmus P. ; Maderia, Matthew P. ; Hansen, Kasper B.

NMDA receptor ligands have therapeutic potential in neurological and psychiatric disorders. We designed (R)-3-(5-thienyl)carboxamido-2-aminopropanoic acid derivatives with nanomolar agonist potencies at NMDA receptor subtypes (GluN12/A-D). These compounds are superagonists at GluN1/2C compared to glycine and partial to full agonists at GluN1/2A and GluN1/2D but display functional antagonism at GluN1/2B due to low agonist efficacy. Notably, 8d display 864% agonist efficacy at GluN1/2C relative to glycine, and 8j has high potency at GluN1/2A (0.018 μM), GluN1/2C (0.0029 μM), and GluN1/2D (0.016 μM). We evaluated the binding mode in the glycine site using molecular modeling and mutagenesis. In vitro absorption, distribution, metabolism, and excretion (ADME) assays predict high metabolic stability but poor blood-brain barrier permeability. However, an ester prodrug for the carboxylate group of 7j display moderately high blood-brain barrier permeability. The thiophenecarboxamide agonists expand the synthetic pharmacology of NMDA receptors and provide structural insights that facilitate the design of GluN1 agonists with GluN2 subunit-specific activity.

项与 GRIN2C 相关的新闻（医药）

2023-04-12

·生物谷

Nature子刊：竺淑佳研究组揭示NMDA受体功能多样性的分子基础

GluN2D富集表达于下丘脑、杏仁核等与情绪调节密切相关的脑区。竺淑佳研究组发现，GluN1-N2D受体具有一个比其他亚型更闭合的氨基端结构域，从而使它具有较低的通道开放概率。 Nature Structural & Molecular Biology在线发表了中国科学院脑科学与智能技术卓越创新中心竺淑佳研究组撰写的题为Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits的研究论文。该研究结合单颗粒冷冻电镜、质脂体单通道记录、电压钳记录、分子动力学模拟、质谱分析、生化验证等多维度技术，揭示了含GluN2D亚基NMDA受体的门控机制和功能特征，诠释了含GluN2C亚基NMDA受体的不对称几何构象及特异性变构调节的机制。该研究为深度理解NMDA受体不同亚型的功能多样性及开发亚型选择性的小分子药物奠定了理论基础（图1）。 NMDA受体是介导大脑突触信号传递和突触可塑性的离子通道，参与并调控神经系统的发育、学习和记忆，同时，其功能异常与诸多神经或精神疾病的发生发展密切相关，是药物研发的重要靶点。哺乳动物大脑中的不同亚型NMDA受体，其表达分布和生物物理学性质具有多样性。含有GluN2A或GluN2B亚基的受体具有较高的通道开放概率和较低的激动剂亲和力。相反，含有GluN2C或GluN2D亚基的受体具有较低的通道开放概率和较高的激动剂亲和力。然而，决定这些功能多样性的分子基础知之甚少。 GluN2D富集表达于下丘脑、杏仁核等与情绪调节密切相关的脑区。竺淑佳研究组发现，GluN1-N2D受体具有一个比其他亚型更闭合的氨基端结构域，从而使它具有较低的通道开放概率。竞争性拮抗剂R-CPP能够通过撑开谷氨酸结合口袋，进而抑制离子通道的开放。GluN1上的可变剪接5号外显子可以使激动剂结合结构域扭转，从而提高离子通道的开放活性。鉴于GluN1-N2D受体的离子通道开放概率与GluN1-N2A受体相差50倍，研究基于结构在相互作用交界面引入一对二硫键，发现交联显著性地提高了GluN1-N2D受体的通道活性。上述成果揭示了GluN1-N2D亚型的门控机制以及决定其生物物理特征的分子基础。研究进一步发现，GluN1-N2C受体采取了与经典NMDA受体所不同的特殊非对称构象。该特性决定了小分子药物PYD-106只能结合相同基因编码的两个GluN2C中的一个亚基。此外，研究还解析了在小脑颗粒细胞中高表达的GluN1-N2A-N2C受体的结构。进一步分析发现，GluN1-N2A-N2C受体中的GluN2A和GluN2C亚基分别整合了对应二异四聚体中的一个单体构象。该研究首次揭示了GluN1-N2C受体的特殊非对称几何学特性，阐释了小分子PYD-106选择性作用于GluN1-N2C受体的机制。　　研究工作得到科技部、国家自然科学基金委员会、中科院、上海市科学技术委员会的支持。　　图1.决定不同NMDA受体功能多样性的分子基础。a、不同NMDA亚型在不同发育阶段的全脑分布（引自Paoletti et al., 2013）；b-c、不同NMDA受体亚型的三维结构及决定功能多样性的结构基础。

2023-03-30

·生物谷

竺淑佳团队揭示NMDA受体功能多样性的分子基础

2023年3月24日，Nature Structural & Molecular Biology期刊在线发表了中国科学院脑科学与智能技术卓越创新中心（神经科学研究所）竺淑佳研究组题为Disti 该研究结合单颗粒冷冻电镜、质脂体单通道记录、电压钳记录、分子动力学模拟、质谱分析、生化验证等多维度技术，揭示了含GluN2D亚基NMDA受体的门控机制和功能特征，诠释了含GluN2C亚基NMDA受体的不对称几何构象及特异性变构调节的机制。该研究为深度理解NMDA受体不同亚型的功能多样性及开发亚型选择性的小分子药物提供了理论基础(图1)。图1.决定不同NMDA受体功能多样性的分子基础。a,不同NMDA亚型在不同发育阶段的全脑分布(引自Paoletti et al., 2013)。b,c,不同NMDA受体亚型的三维结构及决定功能多样性的结构基础。 NMDA受体是介导大脑突触信号传递和突触可塑性的离子通道，参与并调控神经系统的发育、学习和记忆。其功能异常与诸多神经或精神疾病的发生发展密切相关，是药物研发的重要靶点。哺乳动物大脑中的不同亚型NMDA受体，其表达分布和生物物理学性质具有多样性。含有GluN2A或GluN2B亚基的受体具有较高的通道开放概率和较低的激动剂亲和力。相反，含有GluN2C 或GluN2D亚基的受体具有较低的通道开放概率和较高的激动剂亲和力。但是，决定这些功能多样性的分子基础知之甚少。 GluN2D富集表达于下丘脑，杏仁核等与情绪调节密切相关的脑区。竺淑佳研究团队发现，GluN1-N2D受体具有一个比其他亚型更闭合的氨基端结构域，从而使它具有较低的通道开放概率。竞争性拮抗剂R-CPP能够通过撑开谷氨酸结合口袋，进而抑制离子通道的开放。GluN1上的可变剪接5号外显子可以使激动剂结合结构域扭转，从而提高离子通道的开放活性。鉴于GluN1-N2D受体的离子通道开放概率与GluN1-N2A受体相差50倍，研究团队基于结构在相互作用交界面引入一对二硫键，发现交联显著性地提高了GluN1-N2D受体的通道活性（图2a-2d）。以上发现揭示了GluN1-N2D亚型的门控机制以及决定其生物物理特征的分子基础。研究团队进一步发现，GluN1-N2C受体采取了与经典NMDA受体所不同的特殊非对称构象，该特性也决定了小分子药物PYD-106只能结合相同基因编码的两个GluN2C中的一个亚基（图2e,2f）。此外，研究团队还解析了在小脑颗粒细胞中高表达的GluN1-N2A-N2C受体的结构。进一步分析发现，GluN1-N2A-N2C受体中的GluN2A和GluN2C亚基分别整合了对应二异四聚体中的一个单体构象（图2g）。该研究首次揭示了GluN1-N2C受体的特殊非对称几何学特性，深度阐明了小分子PYD-106选择性作用于GluN1-N2C受体的机制。

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