A negative allosteric modulator modulates GABA(B)-receptor signalling through GB2 subunits
文献类型：期刊论文
| 作者 | Sun, Bing2,3; Chen, Linhai1 ; Liu, Lei2,3; Xia, Zhixiong2,3; Pin, Jean-Philippe4; Nan, Fajun1; Liu, Jianfeng2,3
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| 刊名 | BIOCHEMICAL JOURNAL
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| 出版日期 | 2016-03-15 |
| 卷号 | 473页码:779-787 |
| 关键词 | cerebellar granular neurons GABA(B)-receptor heptahelical domain negative allosteric modulator |
| ISSN号 | 0264-6021 |
| DOI | 10.1042/BJ20150979 |
| 文献子类 | Article |
| 英文摘要 | An gamma-aminobutyric acid type B (GABA(B))-receptor mediates slow and prolonged synaptic inhibition in the central nervous system, which represents an interesting target for the treatment of various diseases and disorders of the central nervous system. To date, only one activator of the GABA(B)-receptor, baclofen, is on the market for the treatment of spasticity. Inhibitors of the GABA(B)-receptor, such as antagonists, show anti-absence seizure activity and procognitive properties. In a search for allosteric compounds of the GABA(B)-receptor, although several positive allosteric modulators have been developed, it is only recently that the first negative allosteric modulator (NAM), CLH304a (also named Compound 14), has been reported. In the present study, we provide further information on the mechanism of action of CLH304a, and also show the possibility of designing more NAMs, such as CLH391 and CLH393, based on the structure of CLH304a. First we show that CLH304a inhibits native GABA(B)-receptor activity in cultured cerebellar granular neurons. We then show that CLH304a has inverse agonist properties and non-competitively inhibits the effect of agonists, indicating that it binds at a different site to GABA. The GABA(B)-receptor is a mandatory heterodimer made of GB1 subunits, in which agonists bind, and GB2 subunits, which activate G-proteins. By using various combinations made up of wild-type and/or mutated GB1 and GB2 subunits, we show that CLH304a acts on the heptahelical domain of GB2 subunits. These data revealed the possibility of designing innovative NAMs acting in the heptahelical domain of the GB2 subunits, offering novel possibilities for therapeutic intervention based on GABA(B)-receptor inhibition. |
| WOS关键词 | GABA-B RECEPTORS ; N,N'-DICYCLOPENTYL-2-METHYLSULFANYL-5-NITRO-PYRIMIDINE-4,6-DIAMINE GS39783 ; HEPTAHELICAL DOMAIN ; ACID(B) RECEPTORS ; C-TERMINI ; GAMMA ; PHARMACOLOGY ; ANTAGONIST ; ACTIVATION ; GLUTAMATE |
| 资助项目 | National Natural Science Foundation of China[NSFC] ; Ministry of Science and Technology[2012CB518000] ; Program of Introducing Talents of Discipline to the Universities of the Ministry of Education[B08029] ; Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT)[IRT13016] ; Natural Science Foundation of Hubei province[2014CFA010] ; Merieux Research Grants Program of Institut-Merieux[00000000] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000377208100011 |
| 出版者 | PORTLAND PRESS LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276100]  |
| 专题 | 国家新药筛选中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Nan, Fajun; Liu, Jianfeng |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 200031, Peoples R China; 2.Huazhong Univ Sci & Technol, Coll Life Sci & Technol, Cellular Signalling Lab, Key Lab Mol Biophys,Minist Educ, Wuhan 430074, Peoples R China; 3.Huazhong Univ Sci & Technol, Collaborat Innovat Ctr Brain Sci, Wuhan 430074, Peoples R China; 4.Univ Montpellier 1&2, CNRS, MMR 5203, Inst Genom Fonct, F-34094 Montpellier 5, France |
| 推荐引用方式 GB/T 7714 | Sun, Bing,Chen, Linhai,Liu, Lei,et al. A negative allosteric modulator modulates GABA(B)-receptor signalling through GB2 subunits[J]. BIOCHEMICAL JOURNAL,2016,473:779-787. |
| APA | Sun, Bing.,Chen, Linhai.,Liu, Lei.,Xia, Zhixiong.,Pin, Jean-Philippe.,...&Liu, Jianfeng.(2016).A negative allosteric modulator modulates GABA(B)-receptor signalling through GB2 subunits.BIOCHEMICAL JOURNAL,473,779-787. |
| MLA | Sun, Bing,et al."A negative allosteric modulator modulates GABA(B)-receptor signalling through GB2 subunits".BIOCHEMICAL JOURNAL 473(2016):779-787. |
入库方式： OAI收割
来源：上海药物研究所
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