The Bile Acid Receptor TGR5 (Gpbar-1) Acts as a Neurosteroid Receptor in Brain
The Bile Acid Receptor TGR5 (Gpbar-1) Acts as a Neurosteroid Receptor in Brain
复制标题
DOI：
10.1002/glia.21049
复制
发表时间：
2010-11-15
期刊：
影响因子：
6.2
通讯作者：
Haeussinger, Dieter
中科院分区：
文献类型：
--
作者：
Keitel, Verena;Goerg, Boris;Haeussinger, Dieter
TGR5 (Gpbar-1) 是胃肠道和免疫细胞中的一种膜结合胆汁酸受体，具有多效性。如本研究所示，TGR5也在星形胶质细胞和神经元中表达。在这里，TGR5可能充当神经类固醇受体，它被纳摩尔浓度的5β-pregnan-3α-ol-20-one和微摩尔浓度的5β-pregnan-3α-17α-21-triol-20-one和5α-pregnan-3α-ol-20-one（别孕酮）激活。星形胶质细胞和神经元中的 TGR5 刺激与腺苷酸环化酶激活、细胞内 Ca2+ 升高和活性氧的产生有关。在培养的大鼠星形胶质细胞中，在浓度为 0.5 mmol L-1 的神经类固醇和氨存在下，TGR5 mRNA 下调。此外，与氨一起孵育后，分离的大鼠星形胶质细胞中的 TGR5 蛋白水平显着降低。与非肝硬化对照受试者的大脑相比，死于肝性脑病 (HE) 的肝硬化患者的大脑皮层中也发现 TGR5 mRNA 显着下调。结论是，TGR5 是大脑中一种新型神经类固醇受体，与 HE 的发病机制有关。 (C) 2010 Wiley-Liss, Inc.
TGR5 (Gpbar-1) is a membrane-bound bile acid receptor in the gastrointestinal tract and immune cells with pleiotropic actions. As shown in the present study, TGR5 is also expressed in astrocytes and neurons. Here, TGR5 may act as a neurosteroid receptor, which is activated by nanomolar concentrations of 5 beta-pregnan-3 alpha-ol-20-one and micromolar concentrations of 5 beta-pregnan-3 alpha-17 alpha-21-triol-20-one and 5 alpha-pregnan-3 alpha-ol-20-one (allopregnanolone). TGR5 stimulation in astrocytes and neurons is coupled to adenylate cyclase activation, elevation of intracellular Ca2+ and the generation of reactive oxygen species. In cultured rat astrocytes, TGR5 mRNA is downregulated in the presence of neurosteroids and ammonia already at concentrations of 0.5 mmol L-1. Furthermore, TGR5 protein levels are significantly reduced in isolated rat astrocytes after incubation with ammonia. A marked downregulation of TGR5 mRNA is also found in cerebral cortex from cirrhotic patients dying with hepatic encephalopathy (HE) when compared with brains from noncirrhotic control subjects. It is concluded that TGR5 is a novel neurosteroid receptor in brain with implications for the pathogenesis of HE. (C) 2010 Wiley-Liss, Inc.