Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory
文献类型：期刊论文
| 作者 | Hait, Nitai C.1,2; Wise, Laura E.3; Allegood, Jeremy C.1,2; O'Brien, Megan3; Avni, Dorit1,2; Reeves, Thomas M.4; Knapp, Pamela E.4; Lu, Junyan5; Luo, Cheng5 ; Miles, Michael F.3
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| 刊名 | NATURE NEUROSCIENCE
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| 出版日期 | 2014-07 |
| 卷号 | 17期号:7页码:971-980 |
| ISSN号 | 1097-6256 |
| DOI | 10.1038/nn.3728 |
| 文献子类 | Article |
| 英文摘要 | FTY720 (fingolimod), an FDA-approved drug for treatment of multiple sclerosis, has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. We show that FTY720 enters the nucleus, where it is phosphorylated by sphingosine kinase 2 (SphK2), and that nuclear FTY720-P binds and inhibits class I histone deacetylases (HDACs), enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in the brain, including the hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning, and rescues memory deficits independently of its immunosuppressive actions. Sphk2(-/-) mice have lower levels of hippocampal sphingosine-l-phosphate, an endogenous HDAC inhibitor, and reduced histone acetylation, and display deficits in spatial memory and impaired contextual fear extinction. Thus, sphingosine-l-phosphate and SphK2 play specific roles in memory functions and FTY720 may be a useful adjuvant therapy to facilitate extinction of aversive memories. |
| WOS关键词 | CENTRAL-NERVOUS-SYSTEM ; LONG-TERM-MEMORY ; MULTIPLE-SCLEROSIS ; EPIGENETIC MECHANISMS ; SYNAPTIC PLASTICITY ; CONDITIONED FEAR ; SPHINGOSINE-1-PHOSPHATE ; BDNF ; ACETYLATION ; FTY720 |
| 资助项目 | US National Institutes of Health (NIH)[R37GM043880] ; NIH[P30CA16059] ; National Natural Science Foundation of China[91029704] ; [5P01DA009789] ; [R21AG042745] ; [R01NS057758] |
| WOS研究方向 | Neurosciences & Neurology |
| 语种 | 英语 |
| WOS记录号 | WOS:000338097200014 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277012]  |
| 专题 | 药物发现与设计中心 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 | Spiegel, Sarah |
| 作者单位 | 1.Virginia Commonwealth Univ, Sch Med, Dept Biochem & Mol Biol, Richmond, VA 23284 USA; 2.Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA USA; 3.Virginia Commonwealth Univ, Sch Med, Dept Pharmacol & Toxicol, Richmond, VA USA; 4.Virginia Commonwealth Univ, Sch Med, Dept Anat & Neurobiol, Richmond, VA USA; 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200031, Peoples R China |
| 推荐引用方式 GB/T 7714 | Hait, Nitai C.,Wise, Laura E.,Allegood, Jeremy C.,et al. Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory[J]. NATURE NEUROSCIENCE,2014,17(7):971-980. |
| APA | Hait, Nitai C..,Wise, Laura E..,Allegood, Jeremy C..,O'Brien, Megan.,Avni, Dorit.,...&Spiegel, Sarah.(2014).Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory.NATURE NEUROSCIENCE,17(7),971-980. |
| MLA | Hait, Nitai C.,et al."Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory".NATURE NEUROSCIENCE 17.7(2014):971-980. |
入库方式： OAI收割
来源：上海药物研究所
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