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Identification of a Subtype-Selective Allosteric Inhibitor of GluN1/GluN3 NMDA Receptors

文献类型：期刊论文

作者Zeng, Yue4,5; Zheng, Yueming5; Zhang, Tongtong3,4; Ye, Fei2; Zhan, Li5; Kou, Zengwei3; Zhu, Shujia3,4; Gao, Zhaobing1,4,5
刊名FRONTIERS IN PHARMACOLOGY
出版日期2022-06-09
卷号13页码:13
关键词N-methyl-D-aspartate (NMDA) receptors GluN3 subunits WZB117 allosteric modulator ion channels drug discovery
DOI10.3389/fphar.2022.888308
通讯作者Zhu, Shujia(shujiazhu@ion.ac.cn) ; Gao, Zhaobing(zbgao@simm.ac.cn)
英文摘要N-methyl-D-aspartate receptors (NMDARs) are Ca2+-permeable ionotropic glutamate receptors (iGluRs) in the central nervous system and play important roles in neuronal development and synaptic plasticity. Conventional NMDARs, which typically comprise GluN1 and GluN2 subunits, have different biophysical properties than GluN3-containing NMDARs: GluN3-containing NMDARs have smaller unitary conductance, less Ca2+-permeability and lower Mg2+-sensitivity than those of conventional NMDARs. However, there are very few specific modulators for GluN3-containing NMDARs. Here, we developed a cell-based high-throughput calcium assay and identified 3-fluoro-1,2-phenylene bis (3-hydroxybenzoate) (WZB117) as a relatively selective inhibitor of GluN1/GluN3 receptors. The IC50 value of WZB117 on GluN1/GluN3A receptors expressed in HEK-293 cells was 1.15 +/- 0.34 mu M. Consistently, WZB117 exhibited strong inhibitory activity against glycine-induced currents in the presence of CGP-78608 but only slightly affected the NMDA-, KA- and AMPA-induced currents in the acutely isolated rat hippocampal neurons. Among the four types of endogenous currents, only the first one is primarily mediated by GluN1/GluN3 receptors. Mechanistic studies showed that WZB117 inhibited the GluN1/GluN3A receptors in a glycine-, voltage- and pH-independent manner, suggesting it is an allosteric modulator. Site-directed mutagenesis and chimera construction further revealed that WZB117 may act on the GluN3A pre-M1 region with key determinants different from those of previously identified modulators. Together, our study developed an efficient method to discover modulators of GluN3-containing NMDARs and characterized WZB117 as a novel allosteric inhibitor of GluN1/GluN3 receptors.
WOS关键词GLUN3A EXPRESSION ; SYNAPTIC PLASTICITY ; REGIONAL EXPRESSION ; SPINE DENSITY ; SUBUNIT ; MODULATION ; DISEASE ; NR3A ; ANTAGONISTS ; FLUPIRTINE
资助项目National Science Fund for Distinguished Young Scholars[81825021] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2020284] ; Science and Technology Commission of Shanghai Municipality[19431906000] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB32020000] ; National Natural Science Foundation of China[32100762]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者FRONTIERS MEDIA SA
WOS记录号WOS:000815023200001
源URL[http://119.78.100.183/handle/2S10ELR8/301620]  
专题中国科学院上海药物研究所
通讯作者Zhu, Shujia; Gao, Zhaobing
作者单位1.Chinese Acad Sci, Inst Drug Discovery Innovat, Zhongshan Inst Drug Discovery, Zhongshan, Peoples R China
2.Zhejiang Sci Tech Univ, Coll Life Sci & Med, Hangzhou, Peoples R China
3.Chinese Acad Sci, Inst Neurosci, CAS Ctr Excellence Brain Sci & Intelligence Techno, State Key Lab Neurosci, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, Coll Pharm, Beijing, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Neurol & Psychiat Res & Drug Discovery, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Zeng, Yue,Zheng, Yueming,Zhang, Tongtong,et al. Identification of a Subtype-Selective Allosteric Inhibitor of GluN1/GluN3 NMDA Receptors[J]. FRONTIERS IN PHARMACOLOGY,2022,13:13.
APA Zeng, Yue.,Zheng, Yueming.,Zhang, Tongtong.,Ye, Fei.,Zhan, Li.,...&Gao, Zhaobing.(2022).Identification of a Subtype-Selective Allosteric Inhibitor of GluN1/GluN3 NMDA Receptors.FRONTIERS IN PHARMACOLOGY,13,13.
MLA Zeng, Yue,et al."Identification of a Subtype-Selective Allosteric Inhibitor of GluN1/GluN3 NMDA Receptors".FRONTIERS IN PHARMACOLOGY 13(2022):13.

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来源：上海药物研究所

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