GPRC6A Mediates the Non-genomic Effects of Steroids
GPRC6A Mediates the Non-genomic Effects of Steroids
复制标题
DOI：
10.1074/jbc.m110.158063
复制
发表时间：
2010-12-17
影响因子：
4.8
通讯作者：
Quarles, L. Darryl
中科院分区：
文献类型：
--
作者：
Pi, Min;Parrill, Abby L.;Quarles, L. Darryl
介导雄激素非基因组效应的假定G蛋白偶联受体（GPCR）的身份尚不清楚。我们目前在体外和体内的证据表明，孤儿GPRC 6A受体，广泛表达的钙和氨基酸传感GPCR，转导睾酮和其他类固醇的非基因组效应。GPRC 6A的过表达赋予细胞外睾酮在缺乏雄激素受体的HEK-293细胞中非法快速非基因组信号传导应答的能力。相反，在来自GPRC 6A（-/-）小鼠的骨髓基质细胞和siRNA介导的GPRC 6A敲低后的22 Rv 1前列腺癌细胞中，睾酮刺激的ERK快速信号传导和磷酸化减弱。与野生型对照组相比，GPRC 6A（-/-）敲除小鼠在体内对药理剂量睾酮的反应中，在骨髓和睾丸中表现出显著更少的ERK激活和Egr-1表达。此外，睾酮给药导致野生型雄性小鼠中黄体生成素的抑制，但矛盾地刺激GPRC 6A（-/-）缺失小鼠中的血清黄体生成素水平。这些结果表明GPRC 6A在调节雄激素在多种组织中的非基因组效应中具有重要的功能。
The identity of the putative G-protein coupled receptor (GPCR) that mediates the non-genomic effects of androgens is unknown. We present in vitro and in vivo evidence that the orphan GPRC6A receptor, a widely expressed calcium and amino acid sensing GPCR, transduces the non-genomic effects of testosterone and other steroids. Overexpression of GPRC6A imparts the ability of extracellular testosterone to illicit a rapid, non-genomic signaling response in HEK-293 cells lacking the androgen receptor. Conversely, testosterone-stimulated rapid signaling and phosphorylation of ERK is attenuated in bone marrow stromal cells derived from GPRC6A(-/-) mice and in 22Rv1 prostate cancer cells after siRNA-mediated knockdown of GPRC6A. Compared with wild-type controls, GPRC6A(-/-) null mice exhibit significantly less ERK activation and Egr-1 expression in both bone marrow and testis in response to pharmacological doses of testosterone in vivo. In addition, testosterone administration results in suppression of luteinizing hormone in wild-type male mice, but paradoxically stimulates serum luteinizing hormone levels in GPRC6A(-/-) null mice. These results suggest that GPRC6A is functionally important in regulating non-genomic effects of androgens in multiple tissues.