Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones.
Functional effects of polymorphisms on glucocorticoid receptor modulation of human anxiogenic substance-P gene promoter activity in primary amygdala neurones.
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DOI：
10.1016/j.psyneuen.2014.04.017
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发表时间：
2014-09
影响因子：
3.7
通讯作者：
MacKenzie, Alasdair
中科院分区：
文献类型：
--
作者：
Hay, Colin W.;Shanley, Lynne;Davidson, Scott;Cowie, Philip;Lear, Marissa;McGuffin, Peter;Riedel, Gernot;McEwan, Lain J.;MacKenzie, Alasdair
关键词：
在杏仁核中表达或引入神经肽物质- p （SP；由人类和啮齿动物的TAC1基因编码）可诱导啮齿动物的焦虑相关行为。另外，SP主要受体在人体内的药理拮抗作用；NK1是抗焦虑药。在目前的研究中，我们发现Tac1位点在原代大鼠杏仁核神经元中上调，以响应糖皮质激素受体（GR）的激活；这是应激反应的典型组成部分。通过结合生物信息学、电泳迁移迁移试验（EMSA）和报告质粒磁转染大鼠初级杏仁核神经元，我们在人类TAC1启动子中发现了一个高度保守的GR反应序列（2GR），该序列结合GR对地塞米松（Dex）或福斯克林作出反应。我们还在人类启动子中发现了第二个多态GR结合位点，其t等位基因仅在日本和中国人群中发现。我们提出的证据表明，SNPGR的t等位基因通过去隔离或去抑制2GR来增加TAC1启动子的活性。杏仁核TAC1启动子中Dex/forskolin反应元件的鉴定表明，GR激活与焦虑的分子事件链中可能存在联系。此外，可以改变这种反应的SNP的发现可能会对我们理解特定人群中对压力易感性的调节变异的作用产生影响。
Expression or introduction of the neuropeptide substance-P (SP; encoded by the TAC1 gene in humans and Tac1 in rodents) in the amygdala induces anxiety related behaviour in rodents. In addition, pharmacological antagonism of the main receptor of SP in humans; NK1, is anxiolytic. In the current study, we show that the Tac1 locus is up-regulated in primary rat amygdala neurones in response to activation of the glucocorticoid receptor (GR); a classic component of the stress response. Using a combination of bioinformatics, electrophoretic mobility shift assays (EMSA) and reporter plasmid magnetofection into rat primary amygdala neurones we identified a highly conserved GR response sequence (2GR) in the human TAC1 promoter that binds GR in response to dexamethasone (Dex) or forskolin. We also identified a second GR binding site in the human promoter that was polymorphic and whose T-allele is only found in Japanese and Chinese populations. We present evidence that the T-allele of SNPGR increases the activity of the TAC1 promoter through de-sequestration or de-repression of 2GR. The identification of Dex/forskolin response elements in the TAC1 promoter in amygdala neurones suggests a possible link in the chain of molecular events connecting GR activation and anxiety. In addition, the discovery of a SNP which can alter this response may have implications for our understanding of the role of regulatory variation in susceptibility to stress in specific populations.
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影响因子：
10.6
作者：
Michelgard, Asa;Appel, Lieuwe;Fredrikson, Mats
通讯作者：
Fredrikson, Mats
影响因子：
4.1
作者：
HONKANIEMI, J;PELTOHUIKKO, M;HOKFELT, T
通讯作者：
HOKFELT, T
影响因子：
5.8
作者：
Poulain, Marine;Frydman, Nelly;Livera, Gabriel
通讯作者：
Livera, Gabriel
DOI：
10.1126/science.1222794
发表时间：
2012-09-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Maurano MT;Humbert R;Rynes E;Thurman RE;Haugen E;Wang H;Reynolds AP;Sandstrom R;Qu H;Brody J;Shafer A;Neri F;Lee K;Kutyavin T;Stehling-Sun S;Johnson AK;Canfield TK;Giste E;Diegel M;Bates D;Hansen RS;Neph S;Sabo PJ;Heimfeld S;Raubitschek A;Ziegler S;Cotsapas C;Sotoodehnia N;Glass I;Sunyaev SR;Kaul R;Stamatoyannopoulos JA
通讯作者：
Stamatoyannopoulos JA
影响因子：
7.4
作者：
Lewis-Fernandez, Roberto;Hinton, Devon E.;Laria, Amaro J.;Patterson, Elissa H.;Hofmann, Stefan G.;Craske, Michelle G.;Stein, Dan J.;Asnaani, Ann;Liao, Betty
通讯作者：
Liao, Betty