The GPR55 ligand L-α-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation
The GPR55 ligand L-α-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation
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DOI：
10.1096/fj.08-108670
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发表时间：
2009-01-01
期刊：
影响因子：
4.8
通讯作者：
Irving, Andrew J.
中科院分区：
文献类型：
--
作者：
Henstridge, Christopher M.;Balenga, Nariman A. B.;Irving, Andrew J.
内源性磷脂L-α-溶血磷脂酰肌醇（LPI）最近被鉴定为孤儿G蛋白偶联受体55（GPR 55）的新配体。在这项研究中，我们定义了下游信号通路激活LPI在人胚肾（HEK）293细胞系工程稳定表达重组人GPR 55。我们发现，LPI治疗诱导显着的GPR 55内化，并刺激持续的，振荡的Ca 2+释放途径，这是依赖于G α 13，并需要RhoA激活。然后，我们确定这种信号级联导致NFAT（活化T细胞的核因子）家族转录因子的有效活化及其核转位。在GPR 55的大麻素配体活性分析显示，内源性大麻素anandamide和2-arachidonoylglycerol没有明确的效果，但是，经典的CB 1拮抗剂AM 251诱发GPR 55介导的Ca 2+信号。因此，LPI是GPR 55处的有效配体，其可能是LPI介导的信号传导事件和基因表达变化的关键质膜介质。亨斯特里奇角M.，Balenga，N. A. B.，福特湖一、罗斯河，西-地一、Waldhoer，M.，欧文，A. J.GPR55配体L-α-溶血磷脂酰肌醇促进RhoA依赖性Ca 2+信号传导和NFAT活化。FASEB J. 23，183-193（2009）
The endogenous phospholipid L-alpha-lysophosphatidylinositol (LPI) was recently identified as a novel ligand for the orphan G protein-coupled receptor 55 (GPR55). In this study we define the downstream signaling pathways activated by LPI in a human embryonic kidney (HEK) 293 cell line engineered to stably express recombinant human GPR55. We find that treatment with LPI induces marked GPR55 internalization and stimulates a sustained, oscillatory Ca2+ release pathway, which is dependent on G alpha 13 and requires RhoA activation. We then establish that this signaling cascade leads to the efficient activation of NFAT (nuclear factor of activated T cells) family transcription factors and their nuclear translocation. Analysis of cannabinoid ligand activity at GPR55 revealed no clear effect of the endocannabinoids anandamide and 2-arachidonoylglycerol; however, the classical CB1 antagonist AM251 evoked GPR55-mediated Ca2+ signaling. Thus, LPI is a potent and efficacious ligand at GPR55, which is likely to be a key plasma membrane mediator of LPI- mediated signaling events and changes in gene expression.-Henstridge, C. M., Balenga, N. A. B., Ford, L. A., Ross, R. A., Waldhoer, M., Irving, A. J. The GPR55 ligand L-alpha-lysophosphatidylinositol promotes RhoA- dependent Ca2+ signaling and NFAT activation. FASEB J. 23, 183-193 (2009)