• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

促进促死亡 NMDA 受体信号的是 GluN2B C 端，与 Dapk1 无关。

Pro-death NMDA receptor signaling is promoted by the GluN2B C-terminus independently of Dapk1.

机构信息

UK Dementia Research Institute, University of Edinburgh, Edinburgh, United Kingdom.

Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom.

出版信息

Elife. 2017 Jul 21;6:e17161. doi: 10.7554/eLife.17161.

DOI:10.7554/eLife.17161
PMID:28731405
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5544426/
Abstract

Aberrant NMDA receptor (NMDAR) activity contributes to several neurological disorders, but direct antagonism is poorly tolerated therapeutically. The GluN2B cytoplasmic C-terminal domain (CTD) represents an alternative therapeutic target since it potentiates excitotoxic signaling. The key GluN2B CTD-centred event in excitotoxicity is proposed to involve its phosphorylation at Ser-1303 by Dapk1, that is blocked by a neuroprotective cell-permeable peptide mimetic of the region. Contrary to this model, we find that excitotoxicity can proceed without increased Ser-1303 phosphorylation, and is unaffected by Dapk1 deficiency in vitro or following ischemia in vivo. Pharmacological analysis of the aforementioned neuroprotective peptide revealed that it acts in a sequence-independent manner as an open-channel NMDAR antagonist at or near the Mg site, due to its high net positive charge. Thus, GluN2B-driven excitotoxic signaling can proceed independently of Dapk1 or altered Ser-1303 phosphorylation.

摘要

异常的 NMDA 受体（NMDAR）活性与几种神经疾病有关，但直接拮抗在治疗上的耐受性较差。GluN2B 细胞质 C 末端结构域（CTD）代表了一种替代的治疗靶点，因为它增强了兴奋性毒性信号。兴奋性毒性中的关键 GluN2B CTD 中心事件据推测涉及 Dapk1 对其 Ser-1303 的磷酸化，而该磷酸化被该区域的神经保护细胞可渗透肽模拟物所阻断。与该模型相反，我们发现兴奋性毒性可以在没有增加 Ser-1303 磷酸化的情况下进行，并且在体外 Dapk1 缺乏或体内缺血后不受影响。对上述神经保护肽的药理学分析表明，由于其净正电荷高，它以序列非依赖性方式作为位于或靠近 Mg 位点的开放通道 NMDAR 拮抗剂发挥作用。因此，GluN2B 驱动的兴奋性毒性信号可以独立于 Dapk1 或改变的 Ser-1303 磷酸化进行。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7a1/5544426/31d11fb1847f/elife-17161-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7a1/5544426/3837edcfa27a/elife-17161-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7a1/5544426/007a72c05464/elife-17161-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7a1/5544426/dad24b283789/elife-17161-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7a1/5544426/4398a8da93b0/elife-17161-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7a1/5544426/31d11fb1847f/elife-17161-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7a1/5544426/3837edcfa27a/elife-17161-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7a1/5544426/007a72c05464/elife-17161-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7a1/5544426/dad24b283789/elife-17161-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7a1/5544426/4398a8da93b0/elife-17161-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7a1/5544426/31d11fb1847f/elife-17161-fig3-figsupp1.jpg

相似文献

1
Pro-death NMDA receptor signaling is promoted by the GluN2B C-terminus independently of Dapk1.促进促死亡 NMDA 受体信号的是 GluN2B C 端，与 Dapk1 无关。
Elife. 2017 Jul 21;6:e17161. doi: 10.7554/eLife.17161.
2
Protopanaxadiol ginsenoside Rd protects against NMDA receptor-mediated excitotoxicity by attenuating calcineurin-regulated DAPK1 activity.原人参二醇型皂苷 Rd 通过减弱钙调神经磷酸酶调节的 DAPK1 活性来防止 NMDA 受体介导的兴奋性毒性。
Sci Rep. 2020 May 15;10(1):8078. doi: 10.1038/s41598-020-64738-2.
3
Multiple domains in the C-terminus of NMDA receptor GluN2B subunit contribute to neuronal death following in vitro ischemia.NMDA受体GluN2B亚基C末端的多个结构域在体外缺血后导致神经元死亡。
Neurobiol Dis. 2016 May;89:223-34. doi: 10.1016/j.nbd.2015.11.007. Epub 2015 Nov 12.
4
Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects.解除 DAPK1 与 NMDA 受体 GluN2B 亚基的偶联可迅速发挥抗抑郁样作用。
Mol Psychiatry. 2018 Mar;23(3):597-608. doi: 10.1038/mp.2017.85. Epub 2017 Apr 25.
5
Genetic Mutation of GluN2B Protects Brain Cells Against Stroke Damages.GluN2B 基因突变可保护脑细胞免受中风损伤。
Mol Neurobiol. 2018 Apr;55(4):2979-2990. doi: 10.1007/s12035-017-0562-y. Epub 2017 Apr 29.
6
Involvement of the GluN2A and GluN2B subunits in synaptic and extrasynaptic N-methyl-D-aspartate receptor function and neuronal excitotoxicity.谷氨酸 N-甲基-D-天冬氨酸受体 GluN2A 和 GluN2B 亚基参与突触和非突触型 NMDA 受体功能及神经元兴奋性毒性。
J Biol Chem. 2013 Aug 16;288(33):24151-9. doi: 10.1074/jbc.M113.482000. Epub 2013 Jul 9.
7
The brain-specific tissue-type plasminogen activator inhibitor, neuroserpin, protects neurons against excitotoxicity both in vitro and in vivo.大脑特异性组织型纤溶酶原激活物抑制剂神经丝氨酸蛋白酶抑制剂在体外和体内均可保护神经元免受兴奋性毒性作用。
Mol Cell Neurosci. 2005 Dec;30(4):552-8. doi: 10.1016/j.mcn.2005.09.005. Epub 2005 Oct 4.
8
Neuroprotective effects of a novel single compound 1-methoxyoctadecan-1-ol isolated from Uncaria sinensis in primary cortical neurons and a photothrombotic ischemia model.钩藤中分离得到的新型单化合物 1-甲氧基十八烷-1-醇对原代皮质神经元和光血栓性缺血模型的神经保护作用。
PLoS One. 2014 Jan 8;9(1):e85322. doi: 10.1371/journal.pone.0085322. eCollection 2014.
9
DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke.DAPK1 与 NMDA 受体 NR2B 亚基相互作用介导中风中的脑损伤。
Cell. 2010 Jan 22;140(2):222-34. doi: 10.1016/j.cell.2009.12.055.
10
CaMKII versus DAPK1 Binding to GluN2B in Ischemic Neuronal Cell Death after Resuscitation from Cardiac Arrest.钙调蛋白激酶 II 与钙调蛋白依赖性蛋白激酶 1 对缺血性脑卒中心律骤停复苏后神经元细胞死亡中 GluN2B 的结合作用。
Cell Rep. 2020 Jan 7;30(1):1-8.e4. doi: 10.1016/j.celrep.2019.11.076.

引用本文的文献

1
Innovative approaches for the treatment of stroke: a recent update.中风治疗的创新方法：近期进展
Naunyn Schmiedebergs Arch Pharmacol. 2025 May 29. doi: 10.1007/s00210-025-04288-4.
2
HDAC4 Inhibits NMDA Receptor-mediated Stimulation of Neurogranin Expression.组蛋白去乙酰化酶4抑制N-甲基-D-天冬氨酸受体介导的神经颗粒素表达刺激。
Mol Neurobiol. 2025 May;62(5):5609-5628. doi: 10.1007/s12035-024-04598-3. Epub 2024 Nov 25.
3
The Disruption of NMDAR/TRPM4 Death Signaling with TwinF Interface Inhibitors: A New Pharmacological Principle for Neuroprotection.

本文引用的文献

1
NMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation.NMDA 受体在突触成熟过程中被选择性地分隔成复合物和超复合物。
Nat Commun. 2016 Apr 27;7:11264. doi: 10.1038/ncomms11264.
2
Neuronal development is promoted by weakened intrinsic antioxidant defences due to epigenetic repression of Nrf2.由于Nrf2的表观遗传抑制导致内在抗氧化防御减弱，从而促进神经元发育。
Nat Commun. 2015 May 13;6:7066. doi: 10.1038/ncomms8066.
3
Synaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system.
用双F界面抑制剂破坏NMDAR/TRPM4死亡信号：神经保护的新药理学原理
Pharmaceuticals (Basel). 2023 Jul 31;16(8):1085. doi: 10.3390/ph16081085.
4
GluN2B-containing NMDARs in the mammalian brain: pharmacology, physiology, and pathology.哺乳动物大脑中含GluN2B的N-甲基-D-天冬氨酸受体：药理学、生理学及病理学
Front Mol Neurosci. 2023 May 31;16:1190324. doi: 10.3389/fnmol.2023.1190324. eCollection 2023.
5
Stroke: Molecular mechanisms and therapies: Update on recent developments.中风：分子机制与治疗：最新进展综述。
Neurochem Int. 2023 Jan;162:105458. doi: 10.1016/j.neuint.2022.105458. Epub 2022 Nov 30.
6
NMDA Receptor C-Terminal Domain Signalling in Development, Maturity, and Disease.NMDA 受体 C 端结构域在发育、成熟和疾病中的信号转导。
Int J Mol Sci. 2022 Sep 27;23(19):11392. doi: 10.3390/ijms231911392.
7
Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies.缺血性脑卒中的兴奋性突触传递：经典神经保护策略的新出路。
Int J Mol Sci. 2022 Aug 19;23(16):9381. doi: 10.3390/ijms23169381.
8
Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions.涉及缺血性脑卒中的信号通路：分子机制和治疗干预。
Signal Transduct Target Ther. 2022 Jul 6;7(1):215. doi: 10.1038/s41392-022-01064-1.
9
Cell-penetrating peptide-conjugated Morpholino rescues SMA in a symptomatic preclinical model.细胞穿透肽偶联的 Morpholino 在有症状的临床前模型中拯救 SMA。
Mol Ther. 2022 Mar 2;30(3):1288-1299. doi: 10.1016/j.ymthe.2021.11.012. Epub 2021 Nov 19.
10
Pathophysiological Ionotropic Glutamate Signalling in Neuroinflammatory Disease as a Therapeutic Target.神经炎症性疾病中作为治疗靶点的病理生理离子型谷氨酸信号传导
Front Neurosci. 2021 Oct 21;15:741280. doi: 10.3389/fnins.2021.741280. eCollection 2021.
突触N-甲基-D-天冬氨酸受体活性与谷胱甘肽系统的转录调控相关联。
Nat Commun. 2015 Apr 9;6:6761. doi: 10.1038/ncomms7761.
4
Macromolecular transport in synapse to nucleus communication.大分子在突触到细胞核通讯中的运输。
Trends Neurosci. 2015 Feb;38(2):108-16. doi: 10.1016/j.tins.2014.12.001. Epub 2014 Dec 19.
5
Oligomeric Aβ-induced synaptic dysfunction in Alzheimer's disease.寡聚淀粉样β蛋白诱导的阿尔茨海默病突触功能障碍。
Mol Neurodegener. 2014 Nov 14;9:48. doi: 10.1186/1750-1326-9-48.
6
Phosphorylation and regulation of glutamate receptors by CaMKII.CaMKII对谷氨酸受体的磷酸化作用及调控
Sheng Li Xue Bao. 2014 Jun 25;66(3):365-72.
7
Extrasynaptic NMDA receptor involvement in central nervous system disorders.非突触型 NMDA 受体在中枢神经系统疾病中的作用。
Neuron. 2014 Apr 16;82(2):279-93. doi: 10.1016/j.neuron.2014.03.030.
8
Excitotoxicity and stroke: identifying novel targets for neuroprotection.兴奋性毒性与中风：确定神经保护的新靶点。
Prog Neurobiol. 2014 Apr;115:157-88. doi: 10.1016/j.pneurobio.2013.11.006. Epub 2013 Dec 17.
9
Age-dependent regulation of synaptic connections by dopamine D2 receptors.多巴胺 D2 受体对突触连接的年龄依赖性调节。
Nat Neurosci. 2013 Nov;16(11):1627-36. doi: 10.1038/nn.3542. Epub 2013 Oct 13.
10
Influence of GluN2 subunit identity on NMDA receptor function.GluN2 亚单位组成对 NMDA 受体功能的影响。
Neuropharmacology. 2013 Nov;74:4-17. doi: 10.1016/j.neuropharm.2013.01.016. Epub 2013 Jan 31.