更新于：2024-11-01

GRIN2C

更新于：2024-11-01

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 NMDA receptor complexes that function as heterotetrameric, ligand-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Channel activation requires binding of the neurotransmitter glutamate to the epsilon subunit, glycine binding to the zeta subunit, plus membrane depolarization to eliminate channel inhibition by Mg(2+) (PubMed:26875626). Sensitivity to glutamate and channel kinetics depend on the subunit composition (Probable). Plays a role in regulating the balance between excitatory and inhibitory activity of pyramidal neurons in the prefrontal cortex. Contributes to the slow phase of excitatory postsynaptic current, long-term synaptic potentiation, and learning (By similarity).

关联

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-

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-1105

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-

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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489

项与 GRIN2C 相关的文献（医药）

2024-09-01·British Journal of Pharmacology

Sevoflurane acts as an antidepressant by suppression of GluN2D‐containing NMDA receptors on interneurons

Article

作者: Li, Yuanxi ; Song, Yingcai ; Li, Tianyu ; Zhang, Bing ; Guo, Fei ; Cao, Hang ; Zhou, Xianjin ; Li, Qian ; Du, Weijia ; Zheng, Yinli ; Zhu, Shujia ; Li, Yang ; Zhang, Yongmei ; Liu, Wei ; Shen, Fuyi ; Liu, Zhiqiang

Background and PurposeSevoflurane, a commonly used inhaled anaesthetic known for its favourable safety profile and rapid onset and offset, has not been thoroughly investigated as a potential treatment for depression. In this study, we reveal the mechanism through which sevoflurane delivers enduring antidepressant effects.Experimental ApproachTo assess the antidepressant effects of sevoflurane, behavioural tests were conducted, along with in vitro and ex vivo whole‐cell patch‐clamp recordings, to examine the effects on GluN1–GluN2 incorporated N‐methyl‐d‐aspartate (NMDA) receptors (NMDARs) and neuronal circuitry in the medial prefrontal cortex (mPFC). Multiple‐channel electrophysiology in freely moving mice was performed to evaluate sevoflurane's effects on neuronal activity, and GluN2D knockout (grin2d−/−) mice were used to confirm the requirement of GluN2D for the antidepressant effects.Key ResultsRepeated exposure to subanaesthetic doses of sevoflurane produced sustained antidepressant effects lasting up to 2 weeks. Sevoflurane preferentially inhibited GluN2C‐ and GluN2D‐containing NMDARs, causing a reduction in interneuron activity. In contrast, sevoflurane increased action potentials (AP) firing and decreased spontaneous inhibitory postsynaptic current (sIPSC) in mPFC pyramidal neurons, demonstrating a disinhibitory effect. These effects were absent in grin2d−/− mice, and both pharmacological blockade and genetic knockout of GluN2D abolished sevoflurane's antidepressant actions, suggesting that GluN2D is essential for its antidepressant effect.Conclusion and ImplicationsSevoflurane directly targets GluN2D, leading to a specific decrease in interneuron activity and subsequent disinhibition of pyramidal neurons, which may underpin its antidepressant effects. Targeting the GluN2D subunit could hold promise as a potential therapeutic strategy for treating depression.

2024-08-01·Progress in Neuro-Psychopharmacology and Biological Psychiatry

Probing cognitive flexibility in Shank2-deficient mice: Effects of D-cycloserine and NMDAR signaling hub dynamics

Article

作者: Afzal, Samia ; Dieterich, Daniela C ; Hassan, Iman ; Fendt, Markus ; Soleimanpour, Elaheh ; Tsai, Pei-Ling ; Dürrast, Nora

Neurodevelopmental disorders such as autism spectrum disorder (ASD) have a heterogeneous etiology but are largely associated with genetic factors. Robust evidence from recent human genetic studies has linked mutations in the Shank2 gene to idiopathic ASD. Modeling these Shank2 mutations in animal models recapitulates behavioral changes, e.g. impaired social interaction and repetitive behavior of ASD patients. Shank2-deficient mice exhibit NMDA receptor (NMDAR) hypofunction and associated behavioral deficits. Of note, NMDARs are strongly implicated in cognitive flexibility. Their hypofunction, e.g. observed in schizophrenia, or their pharmacological inhibition leads to impaired cognitive flexibility. However, the association between Shank2 mutations and cognitive flexibility is poorly understood. Using Shank2-deficient mice, we explored the role of Shank2 in cognitive flexibility measured by the attentional set shifting task (ASST) and whether ASST performance in Shank2-deficient mice can be modulated by treatment with the partial NMDAR agonist D-cycloserine (DCS). Furthermore, we investigated the effects of Shank2 deficiency, ASST training, and DCS treatment on the expression level of NMDAR signaling hub components in the orbitofrontal cortex (OFC), including NMDAR subunits (GluN2A, GluN2B, GluN2C), phosphoglycerate dehydrogenase and serine racemase. Surprisingly, Shank2 deficiency did not affect ASST performance or alter the expression of the investigated NMDAR signaling hub components. Importantly, however, DCS significantly improved ASST performance, demonstrating that positive NMDAR modulation facilitates cognitive flexibility. Furthermore, DCS increased the expression of GluN2A in the OFC, but not that of other NMDAR signaling hub components. Our findings highlight the potential of DCS as a pharmacological intervention to improve cognitive flexibility impairments downstream of NMDAR modulation and substantiate the key role of NMDAR in cognitive flexibility.

2024-07-01·Epilepsia

Pathogenic MTOR somatic variant causing focal cortical dysplasia drives hyperexcitability via overactivation of neuronal GluN2C N‐methyl‐D‐aspartate receptors

Article

作者: Bauer, Sylvian ; Pineau, Louison ; Cardoso, Carlos ; Buhler, Emmanuelle ; Watrin, Françoise ; Tarhini, Sarah ; Burnashev, Nail ; Crepel, Valérie ; Represa, Alfonso ; Szepetowski, Pierre

AbstractObjectiveGenetic variations in proteins of the mechanistic target of rapamycin (mTOR) pathway cause a spectrum of neurodevelopmental disorders often associated with brain malformations and with intractable epilepsy. The mTORopathies are characterized by hyperactive mTOR pathway and comprise tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type II. How hyperactive mTOR translates into abnormal neuronal activity and hypersynchronous network remains to be better understood. Previously, the role of upregulated GluN2C‐containing glutamate‐gated N‐methyl‐D‐aspartate receptors (NMDARs) has been demonstrated for germline defects in the TSC genes. Here, we questioned whether this mechanism would expand to other mTORopathies in the different context of a somatic genetic variation of the MTOR protein recurrently found in FCD type II.MethodsWe used a rat model of FCD created by in utero electroporation of neural progenitors of dorsal telencephalon with expression vectors encoding either the wild‐type or the pathogenic MTOR variant (p.S2215F). In this mosaic configuration, patch‐clamp whole‐cell recordings of the electroporated, spiny stellate neurons and extracellular recordings of the electroporated areas were performed in neocortical slices. Selective inhibitors were used to target mTOR activity and GluN2C‐mediated currents.ResultsNeurons expressing the mutant protein displayed an excessive activation of GluN2C NMDAR‐mediated spontaneous excitatory postsynaptic currents. GluN2C‐dependent increase in spontaneous spiking activity was detected in the area of electroporated neurons in the mutant condition and was restricted to a critical time window between postnatal days P9 and P20.SignificanceSomatic MTOR pathogenic variant recurrently found in FCD type II resulted in overactivation of GluN2C‐mediated neuronal NMDARs in neocortices of rat pups. The related and time‐restricted local hyperexcitability was sensitive to subunit GluN2C‐specific blockade. Our study suggests that GluN2C‐related pathomechanisms might be shared in common by mTOR‐related brain disorders.

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。