Retrograde transport of the transmembrane estrogen receptor, G-protein-coupled-receptor-30 (GPR30/GPER) from the plasma membrane towards the nucleus
Retrograde transport of the transmembrane estrogen receptor, G-protein-coupled-receptor-30 (GPR30/GPER) from the plasma membrane towards the nucleus
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DOI：
10.1016/j.steroids.2011.02.018
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发表时间：
2011-08-01
期刊：
影响因子：
2.7
通讯作者：
Filardo, Edward J.
中科院分区：
文献类型：
--
作者：
Cheng, Shi-Bin;Graeber, Carl T.;Filardo, Edward J.
g蛋白偶联受体30 （GPR30/GPER）属于7跨膜受体（7TMR）超家族，是最常见的一类表面受体，已知成员约800个。GPER通过膜相关酶促进雌激素结合和快速信号传导，导致cAMP增加，并从乳腺癌细胞中释放肝素结合表皮生长因子（proHB-EGF）。然而，GPER主要定位于乳腺癌细胞内，细胞表面有少量受体，这一观察结果引起了一些关于其作为质膜雌激素受体的潜在作用的争议。利用广泛采用的通过表面标记活细胞跟踪重组7TMRs的方法，我们已经开始表征和比较GPER与其他类似标记的7TMRs的内吞命运。在人胚胎肾HEK-293细胞中异位表达后，这些细胞在雌二醇-17 β刺激下获得刺激cAMP和激活环AMP应答结合蛋白的能力，从而产生功能性GPER。GPER可以通过ha特异性抗体的免疫荧光分析在细胞表面检测到，尽管大部分受体位于细胞内。与β 1AR （β 1肾上腺素能受体）和CXCR4 （C-X-C趋化因子受体4）一样，GPER通过网格蛋白包被的凹坑离开质膜，进入早期核内体。有趣的是，GPER的目的地在7tmr中并不常见，因为它积聚在核周隔室中。像许多7TMR5（约三分之一）一样，GPER从质膜运输是组成的（在没有激动剂的情况下发生）。然而，它在细胞内运输的途径是非常不寻常的，因为7TMRs通常回收到质膜（如β - 1AR）或在溶酶体中降解（如CXCR4）。本文讨论了GPER在核周空间的积累及其通过这种新认识的膜雌激素受体减弱雌激素作用的可能意义。Elsevier Inc.出版。
G-protein-coupled receptor 30 (GPR30/GPER) belongs to the seven transmembrane receptor (7TMR) superfamily, the most common class of surface receptor with approximately 800 known members. GPER promotes estrogen binding and rapid signaling via membrane-associated enzymes resulting in increased cAMP and release of heparan bound epidermal growth factor (proHB-EGF) from breast cancer cells. However, GPER is predominately localized intracellularly in breast cancer cells with minor amounts of receptor on the cell surface, an observation that has caused some controversy regarding its potential role as a plasma membrane estrogen receptor. Using the widely employed approach of tracking recombinant 7TMRs by surface labeling live cells, we have begun to characterize and compare the endocytic fate of GPER to other similarly labeled 7TMRs. Upon ectopic expression in human embryonic kidney HEK-293 cells, functional GPER is generated as these cells acquire the capacity to stimulate cAMP and activate cyclic AMP responsive binding protein in response to estradiol-17 beta stimulation. GPER is detectable on the cell surface by immunofluorescent analysis using HA-specific antibodies, albeit the bulk of the receptor is located intracellularly. Like beta 1AR (beta 1 adrenergic receptor) and CXCR4 (C-X-C chemokine receptor 4), GPER exits the plasma membrane via clathrin-coated pits and enters early endosomes. Interestingly, GPER has a destination that is uncommon among 7TMRs, as it accumulates in a perinuclear compartment. Like many 7TMR5 (approximately one-third), GPER trafficking from the plasma membrane is constitutive (occurs in the absence of agonist). However, its route of intracellular trafficking is highly unusual, as 7TMRs typically recycle to the plasma membrane (e.g. beta 1AR) or are degraded in lysosomes (e.g. CXCR4). The accumulation of GPER in the perinuclear space and its possible significance for attenuating estrogen action via this newly recognized membrane estrogen receptor is discussed herein. Published by Elsevier Inc.