β2肾上腺受体激动剂通过不典型的c-AMP参与的信号通路激活细胞内钙离子
2017/11/20
摘要
β肾上腺素能受体(βARs)是一种G蛋白偶联受体，它参与了机体对激素/神经递质肾上腺素和去甲肾上腺素的生理反应过程，广泛存在于神经系统乃至于全身多个系统。β肾上腺素能受体是很多药物的作用靶点，尤其是βAR和β2AR，哮喘和心血管疾病相关药物作用于这两种受体。β肾上腺素能受体信号通路通过Gαs G蛋白和腺苷酸环化酶和c-AMP依赖的蛋白激酶途径产生作用。然而，也有人认为其它的一些下游通路对于β肾上腺素能受体信号通路发挥正常生理功能是很重要的。使用基于荧光素的钙离子流分析技术结合药理学与基因敲除技术，我们在hek-293细胞中发现了一种以前未被识别的内源性通路，通过β2AR受体激活磷脂酶C和肌醇三磷酸酯(InsP3)受体进而促进大量钙离子由胞内向胞外流动。这条信号通路并没有cAMP, Gαs, Gαi或者其它典型的β2AR受体级联反应的参与，因此这是该受体参与的一条新的信号通路。这条新发现的由β2AR参与的钙离子动员机制对肾上腺素能信号通路、与其它信号通路的交叉作用以及通过βAR受体作用的药物有深远的影响。
β2-Adrenergic receptor activation mobilizes intracellular calcium via a non-canonical cAMP-independent signaling pathway.
Galaz-Montoya M, Wright SJ, Rodriguez GJ, Lichtarge O, Wensel TG.
Abstract
Beta adrenergic receptors (βARs) are G-protein-coupled receptors essential for physiological responses to the hormones/neurotransmitters epinephrine and norepinephrine which are found in the nervous system and throughout the body. They are the targets of numerous widely used drugs, especially in the case of the most extensively studied βAR, β2AR, whose ligands are used for asthma and cardiovascular disease. βARs signal through Gαs G-proteins and via activation of adenylyl cyclase and cAMP-dependent protein kinase, but some alternative downstream pathways have also been proposed that could be important for understanding normal physiological functioning of βAR signaling and its disruption in disease. Using fluorescence-based Ca2+ flux assays combined with pharmacology and gene knock-out methods, we discovered a previously unrecognized endogenous pathway in HEK-293 cells whereby β2AR activation leads to robust Ca2+ mobilization from intracellular stores via activation of phospholipase C and opening of inositol trisphosphate (InsP3) receptors. This pathway did not involve cAMP, Gαs, or Gαi or the participation of the other members of the canonical β2AR signaling cascade and, therefore, constitutes a novel signaling mechanism for this receptor. This newly uncovered mechanism for Ca2+ mobilization by β2AR has broad implications for adrenergic signaling, cross-talk with other signaling pathways, and the effects of βAR-directed drugs.
β肾上腺素能受体(βARs)是一种G蛋白偶联受体，它参与了机体对激素/神经递质肾上腺素和去甲肾上腺素的生理反应过程，广泛存在于神经系统乃至于全身多个系统。β肾上腺素能受体是很多药物的作用靶点，尤其是βAR和β2AR，哮喘和心血管疾病相关药物作用于这两种受体。β肾上腺素能受体信号通路通过Gαs G蛋白和腺苷酸环化酶和c-AMP依赖的蛋白激酶途径产生作用。然而，也有人认为其它的一些下游通路对于β肾上腺素能受体信号通路发挥正常生理功能是很重要的。使用基于荧光素的钙离子流分析技术结合药理学与基因敲除技术，我们在hek-293细胞中发现了一种以前未被识别的内源性通路，通过β2AR受体激活磷脂酶C和肌醇三磷酸酯(InsP3)受体进而促进大量钙离子由胞内向胞外流动。这条信号通路并没有cAMP, Gαs, Gαi或者其它典型的β2AR受体级联反应的参与，因此这是该受体参与的一条新的信号通路。这条新发现的由β2AR参与的钙离子动员机制对肾上腺素能信号通路、与其它信号通路的交叉作用以及通过βAR受体作用的药物有深远的影响。
（复旦大学附属中山医院呼吸内科 包晨 摘译 杨冬 审校）
（J Biol Chem. 2017 16;292(24):9967-9974.）
（J Biol Chem. 2017 16;292(24):9967-9974.）
β2-Adrenergic receptor activation mobilizes intracellular calcium via a non-canonical cAMP-independent signaling pathway.
Galaz-Montoya M, Wright SJ, Rodriguez GJ, Lichtarge O, Wensel TG.
Abstract
Beta adrenergic receptors (βARs) are G-protein-coupled receptors essential for physiological responses to the hormones/neurotransmitters epinephrine and norepinephrine which are found in the nervous system and throughout the body. They are the targets of numerous widely used drugs, especially in the case of the most extensively studied βAR, β2AR, whose ligands are used for asthma and cardiovascular disease. βARs signal through Gαs G-proteins and via activation of adenylyl cyclase and cAMP-dependent protein kinase, but some alternative downstream pathways have also been proposed that could be important for understanding normal physiological functioning of βAR signaling and its disruption in disease. Using fluorescence-based Ca2+ flux assays combined with pharmacology and gene knock-out methods, we discovered a previously unrecognized endogenous pathway in HEK-293 cells whereby β2AR activation leads to robust Ca2+ mobilization from intracellular stores via activation of phospholipase C and opening of inositol trisphosphate (InsP3) receptors. This pathway did not involve cAMP, Gαs, or Gαi or the participation of the other members of the canonical β2AR signaling cascade and, therefore, constitutes a novel signaling mechanism for this receptor. This newly uncovered mechanism for Ca2+ mobilization by β2AR has broad implications for adrenergic signaling, cross-talk with other signaling pathways, and the effects of βAR-directed drugs.
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